Gene products differentially expressed in cancerous cells and their methods of use II

ABSTRACT

The present invention provides polynucleotides, as well as polypeptides encoded thereby, that are differentially expressed in cancer cells. These polynucleotides are useful in a variety of diagnostic and therapeutic methods. The present invention further provides methods of reducing growth of cancer cells. These methods are useful for treating cancer.

SEQUENCE LISTING AND TABLES

A Sequence Listing is provided as part of this specification ontriplicate compact discs, filed concurrently herewith, which compactdiscs named “Copy 1”, “Copy 2”, and “CRF” each of which compact discscontain the following file: “SEQLIST.TXT”, created Feb. 10, 2004, of 18Megabytes, which is incorporated herein by reference in its entirety.

The present application also incorporates by reference Tables 2, 17, 18,41A, 41B, 70A, 70B, 83, 84, 85, 86, 106, 107A, 107B, 110, 114, 130,131A, 131B, 133, 134, 141, 143, 151 and 162 contained on duplicatecompact discs filed concurrently herewith, which compact discs arelabeled “Atty Docket 21302.001 Tables Copy 1” and “Atty Docket 21302.001Tables Copy 2”. The details of these Tables are further described laterin this disclosure. These compact discs were created on Feb. 10, 2004.The sizes of the Tables are as follows: Table 2: 147 kilobytes; Table17: 344 kilobytes; Table 18: 372 kilobytes; Table 41A: 98 kilobytes;Table 41B: 41 kilobytes; Table 70A: 90 kilobytes; Table 70B: 72kilobytes; Table 83: 60 kilobytes; Table 84: 94 kilobytes; Table 85: 251kilobytes; Table 86: 232 kilobytes; Table 106: 148 kilobytes; Table107A: 193 kilobytes; Table 107B: 138 kilobytes; Table 110: 278kilobytes; Table 114: 11 kilobytes; Table 130: 395 kilobytes; Table131A: 569 kilobytes; Table 131B: 354 kilobytes; Table 133: 40 kilobytes;Table 134: 8 kilobytes; Table 141: 402 kilobytes; Table 143: 98kilobytes; Table 151: 8 kilobytes; and Table 162: 684 kilobytes.

FIELD OF THE INVENTION

The present invention relates to polynucleotides of human origin insubstantially isolated form and gene products that are differentiallyexpressed in cancer cells, and uses thereof.

BACKGROUND OF THE INVENTION

Cancer, like many diseases, is not the result of a single, well-definedcause, but rather can be viewed as several diseases, each caused bydifferent aberrations in informational pathways, that ultimately resultin apparently similar pathologic phenotypes. Identification ofpolynucleotides that correspond to genes that are differentiallyexpressed in cancerous, pre-cancerous, or low metastatic potential cellsrelative to normal cells of the same tissue type, provides the basis fordiagnostic tools, facilitates drug discovery by providing for targetsfor candidate agents, and further serves to identify therapeutic targetsfor cancer therapies that are more tailored for the type of cancer to betreated.

Identification of differentially expressed gene products also furthersthe understanding of the progression and nature of complex diseases suchas cancer, and is key to identifying the genetic factors that areresponsible for the phenotypes associated with development of, forexample, the metastatic phenotype. Identification of gene products thatare differentially expressed at various stages, and in various types ofcancers, can both provide for early diagnostic tests, and further serveas therapeutic targets. Additionally, the product of a differentiallyexpressed gene can be the basis for screening assays to identifychemotherapeutic agents that modulate its activity (e.g. its expression,biological activity, and the like).

Early disease diagnosis is of central importance to halting diseaseprogression, and reducing morbidity. Analysis of a patient's tumor toidentify the gene products that are differentially expressed, andadministration of therapeutic agent(s) designed to modulate the activityof those differentially expressed gene products, provides the basis formore specific, rational cancer therapy that may result in diminishedadverse side effects relative to conventional therapies. Furthermore,confirmation that a tumor poses less risk to the patient (e.g., that thetumor is benign) can avoid unnecessary therapies. In short,identification of genes and the encoded gene products that aredifferentially expressed in cancerous cells can provide the basis oftherapeutics, diagnostics, prognostics, therametrics, and the like.

For example, breast cancer is a leading cause of death among women. Oneof the priorities in breast cancer research is the discovery of newbiochemical markers that can be used for diagnosis, prognosis andmonitoring of breast cancer. The prognostic usefulness of these markersdepends on the ability of the marker to distinguish between patientswith breast cancer who require aggressive therapeutic treatment andpatients who should be monitored.

While the pathogenesis of breast cancer is unclear, transformation ofnon-tumorigenic breast epithelium to a malignant phenotype may be theresult of genetic factors, especially in women under 30 (Miki, et al.,Science, 266: 66-71, 1994). However, it is likely that other,non-genetic factors are also significant in the etiology of the disease.Regardless of its origin, breast cancer morbidity increasessignificantly if a lesion is not detected early in its progression.Thus, considerable effort has focused on the elucidation of earlycellular events surrounding transformation in breast tissue. Such efforthas led to the identification of several potential breast cancermarkers.

Thus, the identification of new markers associated with cancer, forexample, breast cancer, and the identification of genes involved intransforming cells into the cancerous phenotype, remains a significantgoal in the management of this disease. In exemplary aspects, theinvention described herein provides cancer diagnostics, prognostics,therametrics, and therapeutics based upon polynucleotides and/or theirencoded gene products.

SUMMARY OF THE INVENTION

The present invention provides methods and compositions useful indetection of cancerous cells, identification of agents that modulate thephenotype of cancerous cells, and identification of therapeutic targetsfor chemotherapy of cancerous cells. Cancerous, breast, colon andprostate cells are of particular interest in each of these aspects ofthe invention. More specifically, the invention provides polynucleotidesin substantially isolated form, as well as polypeptides encoded thereby,that are differentially expressed in cancer cells. Also provided areantibodies that specifically bind the encoded polypeptides. Thesepolynucleotides, polypeptides and antibodies are thus useful in avariety of diagnostic, therapeutic, and drug discovery methods. In someembodiments, a polynucleotide that is differentially expressed in cancercells can be used in diagnostic assays to detect cancer cells. In otherembodiments, a polynucleotide that is differentially expressed in cancercells, and/or a polypeptide encoded thereby, is itself a target fortherapeutic intervention.

Accordingly, the invention features an isolated polynucleotidecomprising a nucleotide sequence having at least 90% sequence identityto an identifying sequence of any one of the sequences set forth hereinor a degenerate variant thereof. In related aspects, the inventionfeatures recombinant host cells and vectors comprising thepolynucleotides of the invention, as well as isolated polypeptidesencoded by the polynucleotides of the invention and antibodies thatspecifically bind such polypeptides.

In other aspects, the invention provides a method for detecting acancerous cell. In general, the method involves contacting a test sampleobtained from a cell that is suspected of being a cancer cell with aprobe for detecting a gene product differentially expressed in cancer.Many embodiments of the invention involve a gene identifiable by orcomprising a sequence selected from the group consisting of SEQ ID NOS:1-23767, contacting the probe and the gene product for a time sufficientfor binding of the probe to the gene product; and comparing a level ofbinding of the probe to the sample with a level of probe binding to acontrol sample obtained from a control cell of known cancerous state. Amodulated (i.e. increased or decreased) level of binding of the probe inthe test cell sample relative to the level of binding in a controlsample is indicative of the cancerous state of the test cell. In certainembodiments, the level of binding of the probe in the test cell sample,usually in relation to at least one control gene, is similar to bindingof the probe to a cancerous cell sample. In certain other embodiments,the level of binding of the probe in the test cell sample, usually inrelation to at least one control gene, is different, i.e. opposite, tobinding of the probe to a non-cancerous cell sample. In specificembodiments, the probe is a polynucleotide probe and the gene product isnucleic acid. In other specific embodiments, the gene product is apolypeptide. In further embodiments, the gene product or the probe isimmobilized on an array.

In another aspect, the invention provides a method for assessing thecancerous phenotype (e.g., metastasis, metastatic potential, aberrantcellular proliferation, and the like) of a cell comprising detectingexpression of a gene product in a test cell sample, wherein the genecomprises or is identifiable using a sequence selected from the groupconsisting of SEQ ID NOS: 1-23767; and comparing a level of expressionof the gene product in the test cell sample with a level of expressionof the gene in a control cell sample. Comparison of the level ofexpression of the gene in the test cell sample relative to the level ofexpression in the control cell sample is indicative of the cancerousphenotype of the test cell sample. In specific embodiments, detection ofgene expression is by detecting a level of an RNA transcript in the testcell sample. In other specific embodiments detection of expression ofthe gene is by detecting a level of a polypeptide in a test sample.

In another aspect, the invention provides a method for suppressing orinhibiting a cancerous phenotype of a cancerous cell, the methodcomprising introducing into a mammalian cell an expression modulatoryagent (e.g. an antisense molecule, small molecule, antibody,neutralizing antibody, inhibitory RNA molecule, etc.) to inhibitexpression of a gene identified by a sequence selected from the groupconsisting of SEQ ID NOS: 1-23767. Inhibition of expression of the geneinhibits development of a cancerous phenotype in the cell. In specificembodiments, the cancerous phenotype is metastasis, aberrant cellularproliferation relative to a normal cell, or loss of contact inhibitionof cell growth. In the context of this invention “expression” of a geneis intended to encompass the expression of an activity of a geneproduct, and, as such, inhibiting expression of a gene includesinhibiting the activity of a product of the gene.

In another aspect, the invention provides a method for assessing thetumor burden of a subject, the method comprising detecting a level of adifferentially expressed gene product in a test sample from a subjectsuspected of or having a tumor, the differentially expressed geneproduct identified by or comprising a sequence selected from the groupconsisting of SEQ ID NOS: 1-23767. Detection of the level of the geneproduct in the test sample is indicative of the tumor burden in thesubject.

In another aspect, the invention provides a method for identifyingagents that modulate (i.e. increase or decrease) the biological activityof a gene product differentially expressed in a cancerous cell, themethod comprising contacting a candidate agent with a differentiallyexpressed gene product, the differentially expressed gene productcorresponding to a sequence selected from the group consisting of SEQ IDNOS: 1-23767; and detecting a modulation in a biological activity of thegene product relative to a level of biological activity of the geneproduct in the absence of the candidate agent. In specific embodiments,the detecting is by identifying an increase or decrease in expression ofthe differentially expressed gene product. In other specificembodiments, the gene product is mRNA or cDNA prepared from the mRNAgene product. In further embodiments, the gene product is a polypeptide.

In another aspect, the invention provides a method of inhibiting growthof a tumor cell by modulating expression of a gene product, where thegene product is encoded by a gene identified by a sequence selected fromthe group consisting of: SEQ ID NOS:1-23767.

These and other objects, advantages, and features of the invention willbecome apparent to those persons skilled in the art upon reading thedetails of the invention as more fully described below.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1B is a comparison of SEQ ID NO:15951 and clone H72034 (SEQ IDNO:15983).

FIG. 2 is a comparison of SEQ ID NO:15982 and clone AA707002 (SEQ IDNO:15984).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides polynucleotides, as well as polypeptidesencoded thereby, that are differentially expressed in cancer cells.Methods are provided in which these polynucleotides and polypeptides areused for detecting and reducing the growth of cancer cells. Alsoprovided are methods in which the polynucleotides and polypeptides ofthe invention are used in a variety of diagnostic and therapeuticapplications for cancer. The invention finds use in the prevention,treatment, detection or research into any cancer, including prostrate,pancreas, colon, brain, lung, breast, bone, skin cancers, etc.

Before the present invention is described, it is to be understood thatthis invention is not limited to particular embodiments described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are now described. All publications and patentapplications mentioned herein are incorporated herein by reference todisclose and describe the methods and/or materials in connection withwhich the publications are cited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “apolynucleotide” includes a plurality of such polynucleotides andreference to “the cancer cell” includes reference to one or more cellsand equivalents thereof known to those skilled in the art, and so forth.

The publications and applications discussed herein are provided solelyfor their disclosure prior to the filing date of the presentapplication. Nothing herein is to be construed as an admission that thepresent invention is not entitled to antedate such publication by virtueof prior invention. Further, the dates of publication provided may bedifferent from the actual publication dates which may need to beindependently confirmed.

Definitions

The terms “polynucleotide” and “nucleic acid”, used interchangeablyherein, refer to polymeric forms of nucleotides of any length, eitherribonucleotides or deoxynucleotides. Thus, these terms include, but arenot limited to, single-, double-, or multi-stranded DNA or RNA, genomicDNA, cDNA, DNA-RNA hybrids, or a polymer comprising purine andpyrimidine bases or other natural, chemically or biochemically modified,non-natural, or derivatized nucleotide bases. These terms furtherinclude, but are not limited to, mRNA or cDNA that comprise intronicsequences (see, e.g., Niwa et al. (1999) Cell 99(7):691-702). Thebackbone of the polynucleotide can comprise sugars and phosphate groups(as may typically be found in RNA or DNA), or modified or substitutedsugar or phosphate groups. Alternatively, the backbone of thepolynucleotide can comprise a polymer of synthetic subunits such asphosphoramidites and thus can be an oligodeoxynucleoside phosphoramidateor a mixed phosphoramidate-phosphodiester oligomer. Peyrottes et al.(1996) Nucl. Acids Res. 24:1841-1848; Chaturvedi et al. (1996) Nucl.Acids Res. 24:2318-2323. A polynucleotide may comprise modifiednucleotides, such as methylated nucleotides and nucleotide analogs,uracyl, other sugars, and linking groups such as fluororibose andthioate, and nucleotide branches. The sequence of nucleotides may beinterrupted by non-nucleotide components. A polynucleotide may befurther modified after polymerization, such as by conjugation with alabeling component. Other types of modifications included in thisdefinition are caps, substitution of one or more of the naturallyoccurring nucleotides with an analog, and introduction of means forattaching the polynucleotide to proteins, metal ions, labelingcomponents, other polynucleotides, or a solid support. The term“polynucleotide” also encompasses peptidic nucleic acids (Pooga et alCurr Cancer Drug Targets. (2001) 1:231-9).

A “gene product” is a biopolymeric product that is expressed or producedby a gene. A gene product may be, for example, an unspliced RNA, anmRNA, a splice variant mRNA, a polypeptide, a post-translationallymodified polypeptide, a splice variant polypeptide etc. Also encompassedby this term is biopolymeric products that are made using an RNA geneproduct as a template (i.e. cDNA of the RNA). A gene product may be madeenzymatically, recombinantly, chemically, or within a cell to which thegene is native. In many embodiments, if the gene product isproteinaceous, it exhibits a biological activity. In many embodiments,if the gene product is a nucleic acid, it can be translated into aproteinaceous gene product that exhibits a biological activity.

A composition (e.g. a polynucleotide, polypeptide, antibody, or hostcell) that is “isolated” or “in substantially isolated form” refers to acomposition that is in an environment different from that in which thecomposition naturally occurs. For example, a polynucleotide that is insubstantially isolated form is outside of the host cell in which thepolynucleotide naturally occurs, and could be a purified fragment ofDNA, could be part of a heterologous vector, or could be containedwithin a host cell that is not a host cell from which the polynucleotidenaturally occurs. The term “isolated” does not refer to a genomic orcDNA library, whole cell total protein or mRNA preparation, genomic DNApreparation, or an isolated human chromosome. A composition which is insubstantially isolated form is usually substantially purified.

As used herein, the term “substantially purified” refers to a compound(e.g., a polynucleotide, a polypeptide or an antibody, etc.) that isremoved from its natural environment and is usually at least 60% free,preferably 75% free, and most preferably 90% free from other componentswith which it is naturally associated. Thus, for example, a compositioncontaining A is “substantially free of” B when at least 85% by weight ofthe total A+B in the composition is A. Preferably, A comprises at leastabout 90% by weight of the total of A+B in the composition, morepreferably at least about 95% or even 99% by weight. In the case ofpolynucleotides, “A” and “B” may be two different genes positioned ondifferent chromosomes or adjacently on the same chromosome, or twoisolated cDNA species, for example.

The terms “polypeptide” and “protein”, interchangeably used herein,refer to a polymeric form of amino acids of any length, which caninclude coded and non-coded amino acids, chemically or biochemicallymodified or derivatized amino acids, and polypeptides having modifiedpeptide backbones. The term includes fusion proteins, including, but notlimited to, fusion proteins with a heterologous amino acid sequence,fusions with heterologous and homologous leader sequences, with orwithout N-terminal methionine residues; immunologically tagged proteins;and the like.

“Heterologous” refers to materials that are derived from differentsources (e.g., from different genes, different species, etc.).

As used herein, the terms “a gene that is differentially expressed in acancer cell,” and “a polynucleotide that is differentially expressed ina cancer cell” are used interchangeably herein, and generally refer to apolynucleotide that represents or corresponds to a gene that isdifferentially expressed in a cancerous cell when compared with a cellof the same cell type that is not cancerous, e.g., mRNA is found atlevels at least about 25%, at least about 50% to about 75%, at leastabout 90%, at least about 1.5-fold, at least about 2-fold, at leastabout 5-fold, at least about 10-fold, or at least about 50-fold or more,different (e.g., higher or lower). The comparison can be made in tissue,for example, if one is using in situ hybridization or another assaymethod that allows some degree of discrimination among cell types in thetissue. The comparison may also or alternatively be made between cellsremoved from their tissue source.

“Differentially expressed polynucleotide” as used herein refers to anucleic acid molecule (RNA or DNA) comprising a sequence that representsa differentially expressed gene, e.g., the differentially expressedpolynucleotide comprises a sequence (e.g., an open reading frameencoding a gene product; a non-coding sequence) that uniquely identifiesa differentially expressed gene so that detection of the differentiallyexpressed polynucleotide in a sample is correlated with the presence ofa differentially expressed gene in a sample. “Differentially expressedpolynucleotides” is also meant to encompass fragments of the disclosedpolynucleotides, e.g., fragments retaining biological activity, as wellas nucleic acids homologous, substantially similar, or substantiallyidentical (e.g., having about 90% sequence identity) to the disclosedpolynucleotides.

“Corresponds to” or “represents” when used in the context of, forexample, a polynucleotide or sequence that “corresponds to” or“represents” a gene means that at least a portion of a sequence of thepolynucleotide is present in the gene or in the nucleic acid geneproduct (e.g., mRNA or cDNA). A subject nucleic acid may also be“identified” by a polynucleotide if the polynucleotide corresponds to orrepresents the gene. Genes identified by a polynucleotide may have allor a portion of the identifying sequence wholly present within an exonof a genomic sequence of the gene, or different portions of the sequenceof the polynucleotide may be present in different exons (e.g., such thatthe contiguous polynucleotide sequence is present in an mRNA, eitherpre- or post-splicing, that is an expression product of the gene). Insome embodiments, the polynucleotide may represent or correspond to agene that is modified in a cancerous cell relative to a normal cell. Thegene in the cancerous cell may contain a deletion, insertion,substitution, or translocation relative to the polynucleotide and mayhave altered regulatory sequences, or may encode a splice variant geneproduct, for example. The gene in the cancerous cell may be modified byinsertion of an endogenous retrovirus, a transposable element, or othernaturally occurring or non-naturally occurring nucleic acid. In mostcases, a polynucleotide corresponds to or represents a gene if thesequence of the polynucleotide is most identical to the sequence of agene or its product (e.g. mRNA or cDNA) as compared to other genes ortheir products. In most embodiments, the most identical gene isdetermined using a sequence comparison of a polynucleotide to a databaseof polynucleotides (e.g. GenBank) using the BLAST program at defaultsettings For example, if the most similar gene in the human genome to anexemplary polynucleotide is the protein kinase C gene, the exemplarypolynucleotide corresponds to protein kinase C. In most cases, thesequence of a fragment of an exemplary polynucleotide is at least 95%,96%, 97%, 98%, 99% or up to 100% identical to a sequence of at least 15,20, 25, 30, 35, 40, 45, or 50 contiguous nucleotides of a correspondinggene or its product (mRNA or cDNA), when nucleotides that are “N”represent G, A, T or C.

An “identifying sequence” is a minimal fragment of a sequence ofcontiguous nucleotides that uniquely identifies or defines apolynucleotide sequence or its complement. In many embodiments, afragment of a polynucleotide uniquely identifies or defines apolynucleotide sequence or its complement. In some embodiments, theentire contiguous sequence of a gene, cDNA, EST, or other providedsequence is an identifying sequence.

“Diagnosis” as used herein generally includes determination of asubject's susceptibility to a disease or disorder, determination as towhether a subject is presently affected by a disease or disorder,prognosis of a subject affected by a disease or disorder (e.g.,identification of pre-metastatic or metastatic cancerous states, stagesof cancer, or responsiveness of cancer to therapy), and use oftherametrics (e.g., monitoring a subject's condition to provideinformation as to the effect or efficacy of therapy).

As used herein, the term “a polypeptide associated with cancer” refersto a polypeptide encoded by a polynucleotide that is differentiallyexpressed in a cancer cell.

The term “biological sample” encompasses a variety of sample typesobtained from an organism and can be used in a diagnostic or monitoringassay. The term encompasses blood and other liquid samples of biologicalorigin, solid tissue samples, such as a biopsy specimen or tissuecultures or cells derived therefrom and the progeny thereof. The termencompasses samples that have been manipulated in any way after theirprocurement, such as by treatment with reagents, solubilization, orenrichment for certain components. The term encompasses a clinicalsample, and also includes cells in cell culture, cell supernatants, celllysates, serum, plasma, biological fluids, and tissue samples.

The terms “treatment”, “treating”, “treat” and the like are used hereinto generally refer to obtaining a desired pharmacologic and/orphysiologic effect. The effect may be prophylactic in terms ofcompletely or partially preventing a disease or symptom thereof and/ormay be therapeutic in terms of a partial or complete stabilization orcure for a disease and/or adverse effect attributable to the disease.“Treatment” as used herein covers any treatment of a disease in amammal, particularly a human, and includes: (a) preventing the diseaseor symptom from occurring in a subject which may be predisposed to thedisease or symptom but has not yet been diagnosed as having it; (b)inhibiting the disease symptom, i.e., arresting its development; or (c)relieving the disease symptom, i.e., causing regression of the diseaseor symptom.

The terms “individual,” “subject,” “host,” and “patient,” usedinterchangeably herein and refer to any mammalian subject for whomdiagnosis, treatment, or therapy is desired, particularly humans. Othersubjects may include cattle, dogs, cats, guinea pigs, rabbits, rats,mice, horses, and the like.

A “host cell”, as used herein, refers to a microorganism or a eukaryoticcell or cell line cultured as a unicellular entity which can be, or hasbeen, used as a recipient for a recombinant vector or other transferpolynucleotides, and include the progeny of the original cell which hasbeen transfected. It is understood that the progeny of a single cell maynot necessarily be completely identical in morphology or in genomic ortotal DNA complement as the original parent, due to natural, accidental,or deliberate mutation.

The terms “cancer”, “neoplasm”, “tumor”, and “carcinoma”, are usedinterchangeably herein to refer to cells which exhibit relativelyautonomous growth, so that they exhibit an aberrant growth phenotypecharacterized by a significant loss of control of cell proliferation. Ingeneral, cells of interest for detection or treatment in the presentapplication include precancerous (e.g., benign), malignant,pre-metastatic, metastatic, and non-metastatic cells. Detection ofcancerous cells is of particular interest.

The term “normal” as used in the context of “normal cell,” is meant torefer to a cell of an untransformed phenotype or exhibiting a morphologyof a non-transformed cell of the tissue type being examined.

“Cancerous phenotype” generally refers to any of a variety of biologicalphenomena that are characteristic of a cancerous cell, which phenomenacan vary with the type of cancer. The cancerous phenotype is generallyidentified by abnormalities in, for example, cell growth orproliferation (e.g., uncontrolled growth or proliferation), regulationof the cell cycle, cell mobility, cell-cell interaction, or metastasis,etc.

“Therapeutic target” generally refers to a gene or gene product that,upon modulation of its activity (e.g., by modulation of expression,biological activity, and the like), can provide for modulation of thecancerous phenotype.

As used throughout, “modulation” is meant to refer to an increase or adecrease in the indicated phenomenon (e.g., modulation of a biologicalactivity refers to an increase in a biological activity or a decrease ina biological activity).

Polynucleotide Compositions

The present invention provides isolated polynucleotides that containnucleic acids that are differentially expressed in cancer cells. Thepolynucleotides, as well as any polypeptides encoded thereby, find usein a variety of therapeutic and diagnostic methods.

The scope of the invention with respect to compositions containing theisolated polynucleotides useful in the methods described hereinincludes, but is not necessarily limited to, polynucleotides having(i.e., comprising) a sequence set forth in any one of the polynucleotidesequences provided herein, or fragment thereof, polynucleotides obtainedfrom the biological materials described herein or other biologicalsources (particularly human sources) by hybridization under stringentconditions (particularly conditions of high stringency); genescorresponding to the provided polynucleotides; cDNAs corresponding tothe provided polynucleotides; variants of the provided polynucleotidesand their corresponding genes, particularly those variants that retain abiological activity of the encoded gene product (e.g., a biologicalactivity ascribed to a gene product corresponding to the providedpolynucleotides as a result of the assignment of the gene product to aprotein family(ies) and/or identification of a functional domain presentin the gene product). Other nucleic acid compositions contemplated byand within the scope of the present invention will be readily apparentto one of ordinary skill in the art when provided with the disclosurehere. “Polynucleotide” and “nucleic acid” as used herein with referenceto nucleic acids of the composition is not intended to be limiting as tothe length or structure of the nucleic acid unless specificallyindicated.

The invention features polynucleotides that represent genes that areexpressed in human tissue, specifically polynucleotides that aredifferentially expressed in tissues containing cancerous cells. Nucleicacid compositions described herein of particular interest are at leastabout 15 bp in length, at least about 30 bp in length, at least about 50bp in length, at least about 100 bp, at least about 200 bp in length, atleast about 300 bp in length, at least about 500 bp in length, at leastabout 800 bp in length, at least about 1 kb in length, at least about2.0 kb in length, at least about 3.0 kb in length, at least about 5 kbin length, at least about 10 kb in length, at least about 50 kb inlength and are usually less than about 200 kb in length. Thesepolynucleotides (or polynucleotide fragments) have uses that include,but are not limited to, diagnostic probes and primers as startingmaterials for probes and primers, as discussed herein.

The subject polynucleotides usually comprise a sequence set forth in anyone of the polynucleotide sequences provided herein, for example, in thesequence listing, incorporated by reference in a table (e.g. by an NCBIaccession number), a cDNA deposited at the A.T.C.C., or a fragment orvariant thereof. A “fragment” or “portion” of a polynucleotide is acontiguous sequence of residues at least about 10 nt to about 12 nt, 15nt, 16 nt, 18 nt or 20 nt in length, usually at least about 22 nt, 24nt, 25 nt, 30 nt, 40 nt, 50 nt, 60 nt, 70 nt, 80 nt, 90 nt, 100 nt to atleast about 150 nt, 200 nt, 250 nt, 300 nt, 350 nt, 400 nt, 500 nt, 800nt or up to about 1000 nt, 1500 or 2000 nt in length. In someembodiments, a fragment of a polynucleotide is the coding sequence of apolynucleotide. A fragment of a polynucleotide may start at position 1(i.e. the first nucleotide) of a nucleotide sequence provided herein, ormay start at about position 10, 20, 30, 50, 75, 100, 150, 200, 250, 300,350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500 or 2000, or an ATGtranslational initiation codon of a nucleotide sequence provided herein.In this context “about” includes the particularly recited value or avalue larger or smaller by several (5, 4, 3, 2, or 1) nucleotides. Thedescribed polynucleotides and fragments thereof find use ashybridization probes, PCR primers, BLAST probes, or as an identifyingsequence, for example.

The subject nucleic acids may be variants or degenerate variants of asequence provided herein. In general, a variants of a polynucleotideprovided herein have a fragment of sequence identity that is greaterthan at least about 65%, greater than at least about 70%, greater thanat least about 75%, greater than at least about 80%, greater than atleast about 85%, or greater than at least about 90%, 95%, 96%, 97%, 98%,99% or more (i.e. 100%) as compared to an identically sized fragment ofa provided sequence. as determined by the Smith-Waterman homology searchalgorithm as implemented in MPSRCH program (Oxford Molecular). For thepurposes of this invention, a preferred method of calculating percentidentity is the Smith-Waterman algorithm. Global DNA sequence identityshould be greater than 65% as determined by the Smith-Waterman homologysearch algorithm as implemented in MPSRCH program (Oxford Molecular)using an gap search with the following search parameters: gap openpenalty, 12; and gap extension penalty, 1.

The subject nucleic acid compositions include full-length cDNAs or mRNAsthat encompass an identifying sequence of contiguous nucleotides fromany one of the polynucleotide sequences provided herein.

As discussed above, the polynucleotides useful in the methods describedherein also include polynucleotide variants having sequence similarityor sequence identity. Nucleic acids having sequence similarity aredetected by hybridization under low stringency conditions, for example,at 50° C. and 10×SSC (0.9 M saline/0.09 M sodium citrate) and remainbound when subjected to washing at 55° C. in 1×SSC. Sequence identitycan be determined by hybridization under high stringency conditions, forexample, at 50° C. or higher and 0.1×SSC (9 mM saline/0.9 mM sodiumcitrate). Hybridization methods and conditions are well known in theart, see, e.g., U.S. Pat. No. 5,707,829. Nucleic acids that aresubstantially identical to the provided polynucleotide sequences, e.g.allelic variants, genetically altered versions of the gene, etc., bindto the provided polynucleotide sequences under stringent hybridizationconditions. By using probes, particularly labeled probes of DNAsequences, one can isolate homologous or related genes. The source ofhomologous genes can be any species, e.g. primate species, particularlyhuman; rodents, such as rats and mice; canines, felines, bovines,ovines, equines, yeast, nematodes, etc.

In one embodiment, hybridization is performed using a fragment of atleast 15 contiguous nucleotides (nt) of at least one of thepolynucleotide sequences provided herein. That is, when at least 15contiguous nt of one of the disclosed polynucleotide sequences is usedas a probe, the probe will preferentially hybridize with a nucleic acidcomprising the complementary sequence, allowing the identification andretrieval of the nucleic acids that uniquely hybridize to the selectedprobe. Probes from more than one polynucleotide sequence provided hereincan hybridize with the same nucleic acid if the cDNA from which theywere derived corresponds to one mRNA.

Polynucleotides contemplated for use in the invention also include thosehaving a sequence of naturally occurring variants of the nucleotidesequences (e.g., degenerate variants (e.g., sequences that encode thesame polypeptides but, due to the degenerate nature of the genetic code,different in nucleotide sequence), allelic variants, etc.). Variants ofthe polynucleotides contemplated by the invention are identified byhybridization of putative variants with nucleotide sequences disclosedherein, preferably by hybridization under stringent conditions. Forexample, by using appropriate wash conditions, variants of thepolynucleotides described herein can be identified where the allelicvariant exhibits at most about 25-30% base pair (bp) mismatches relativeto the selected polynucleotide probe. In general, allelic variantscontain 15-25% bp mismatches, and can contain as little as even 5-15%,or 2-5%, or 1-2% bp mismatches, as well as a single bp mismatch.

The invention also encompasses homologs corresponding to any one of thepolynucleotide sequences provided herein, where the source of homologousgenes can be any mammalian species, e.g., primate species, particularlyhuman; rodents, such as rats; canines, felines, bovines, ovines,equines, yeast, nematodes, etc. Between mammalian species, e.g., humanand mouse, homologs generally have substantial sequence similarity,e.g., at least 75% sequence identity, usually at least 80%%, at least85, at least 90%, at least 95%, at least 96%, at least 97%, at least98%, at least 99% or even 100% identity between nucleotide sequences.Sequence similarity is calculated based on a reference sequence, whichmay be a subset of a larger sequence, such as a conserved motif, codingregion, flanking region, etc. A reference sequence will usually be atleast about a fragment of a polynucleotide sequence and may extend tothe complete sequence that is being compared. Algorithms for sequenceanalysis are known in the art, such as gapped BLAST, described inAltschul, et al. Nucleic Acids Res. (1997) 25:3389-3402, or TeraBLASTavailable from TimeLogic Corp. (Crystal Bay, Nev.).

The subject nucleic acids can be cDNAs or genomic DNAs, as well asfragments thereof, particularly fragments that encode a biologicallyactive gene product and/or are useful in the methods disclosed herein(e.g., in diagnosis, as a unique identifier of a differentiallyexpressed gene of interest, etc.). The term “cDNA” as used herein isintended to include all nucleic acids that share the arrangement ofsequence elements found in native mature mRNA species, where sequenceelements are exons and 3′ and 5′ non-coding regions. Normally mRNAspecies have contiguous exons, with the intervening introns, whenpresent, being removed by nuclear RNA splicing, to create a continuousopen reading frame encoding a polypeptide. mRNA species can also existwith both exons and introns, where the introns may be removed byalternative splicing. Furthermore it should be noted that differentspecies of mRNAs encoded by the same genomic sequence can exist atvarying levels in a cell, and detection of these various levels of mRNAspecies can be indicative of differential expression of the encoded geneproduct in the cell.

A genomic sequence of interest comprises the nucleic acid presentbetween the initiation codon and the stop codon, as defined in thelisted sequences, including all of the introns that are normally presentin a native chromosome. It can further include the 3′ and 5′untranslated regions found in the mature mRNA. It can further includespecific transcriptional and translational regulatory sequences, such aspromoters, enhancers, etc., including about 1 kb, but possibly more, offlanking genomic DNA at either the 5′ and 3′ end of the transcribedregion. The genomic DNA can be isolated as a fragment of 100 kbp orsmaller; and substantially free of flanking chromosomal sequence. Thegenomic DNA flanking the coding region, either 3′ and 5′, or internalregulatory sequences as sometimes found in introns, contains sequencesrequired for proper tissue, stage-specific, or disease-state specificexpression.

The nucleic acid compositions of the subject invention can encode all ora part of the naturally-occurring polypeptides. Double or singlestranded fragments can be obtained from the DNA sequence by chemicallysynthesizing oligonucleotides in accordance with conventional methods,by restriction enzyme digestion, by PCR amplification, etc.

Probes specific to the polynucleotides described herein can be generatedusing the polynucleotide sequences disclosed herein. The probes areusually a fragment of a polynucleotide sequences provided herein. Theprobes can be synthesized chemically or can be generated from longerpolynucleotides using restriction enzymes. The probes can be labeled,for example, with a radioactive, biotinylated, or fluorescent tag.Preferably, probes are designed based upon an identifying sequence ofany one of the polynucleotide sequences provided herein. Morepreferably, probes are designed based on a contiguous sequence of one ofthe subject polynucleotides that remain unmasked following applicationof a masking program for masking low complexity (e.g., XBLAST,RepeatMasker, etc.) to the sequence., i.e., one would select an unmaskedregion, as indicated by the polynucleotides outside the poly-n stretchesof the masked sequence produced by the masking program.

The polynucleotides of interest in the subject invention are isolatedand obtained in substantial purity, generally as other than an intactchromosome. Usually, the polynucleotides, either as DNA or RNA, will beobtained substantially free of other naturally-occurring nucleic acidsequences that they are usually associated with, generally being atleast about 50%, usually at least about 90% pure and are typically“recombinant”, e.g., flanked by one or more nucleotides with which it isnot normally associated on a naturally occurring chromosome.

The polynucleotides described herein can be provided as a linearmolecule or within a circular molecule, and can be provided withinautonomously replicating molecules (vectors) or within molecules withoutreplication sequences. Expression of the polynucleotides can beregulated by their own or by other regulatory sequences known in theart. The polynucleotides can be introduced into suitable host cellsusing a variety of techniques available in the art, such as transferrinpolycation-mediated DNA transfer, transfection with naked orencapsulated nucleic acids, liposome-mediated DNA transfer,intracellular transportation of DNA-coated latex beads, protoplastfusion, viral infection, electroporation, gene gun, calciumphosphate-mediated transfection, and the like.

The nucleic acid compositions described herein can be used to, forexample, produce polypeptides, as probes for the detection of mRNA inbiological samples (e.g., extracts of human cells) or cDNA produced fromsuch samples, to generate additional copies of the polynucleotides, togenerate ribozymes or antisense oligonucleotides, and as single strandedDNA probes or as triple-strand forming oligonucleotides. The probesdescribed herein can be used to, for example, determine the presence orabsence of any one of the polynucleotide provided herein or variantsthereof in a sample. These and other uses are described in more detailbelow.

Polypeptides and Variants Thereof

The present invention further provides polypeptides encoded bypolynucleotides that represent genes that are differentially expressedin cancer cells. Such polypeptides are referred to herein as“polypeptides associated with cancer.” The polypeptides can be used togenerate antibodies specific for a polypeptide associated with cancer,which antibodies are in turn useful in diagnostic methods, prognosticsmethods, therametric methods, and the like as discussed in more detailherein. Polypeptides are also useful as targets for therapeuticintervention, as discussed in more detail herein.

The polypeptides contemplated by the invention include those encoded bythe disclosed polynucleotides and the genes to which thesepolynucleotides correspond, as well as nucleic acids that, by virtue ofthe degeneracy of the genetic code, are not identical in sequence to thedisclosed polynucleotides. Further polypeptides contemplated by theinvention include polypeptides that are encoded by polynucleotides thathybridize to polynucleotide of the sequence listing. Thus, the inventionincludes within its scope a polypeptide encoded by a polynucleotidehaving the sequence of any one of the polynucleotide sequences providedherein, or a variant thereof.

In general, the term “polypeptide” as used herein refers to both thefull length polypeptide encoded by the recited polynucleotide, thepolypeptide encoded by the gene represented by the recitedpolynucleotide, as well as portions or fragments thereof. “Polypeptides”also includes variants of the naturally occurring proteins, where suchvariants are homologous or substantially similar to the naturallyoccurring protein, and can be of an origin of the same or differentspecies as the naturally occurring protein (e.g., human, murine, or someother species that naturally expresses the recited polypeptide, usuallya mammalian species). In general, variant polypeptides have a sequencethat has at least about 80%, usually at least about 90%, and moreusually at least about 98% sequence identity with a differentiallyexpressed polypeptide described herein, as measured by BLAST 2.0 usingthe parameters described above. The variant polypeptides can benaturally or non-naturally glycosylated, i.e., the polypeptide has aglycosylation pattern that differs from the glycosylation pattern foundin the corresponding naturally occurring protein.

The invention also encompasses homologs of the disclosed polypeptides(or fragments thereof) where the homologs are isolated from otherspecies, i.e. other animal or plant species, where such homologs,usually mammalian species, e.g. rodents, such as mice, rats; domesticanimals, e.g., horse, cow, dog, cat; and humans. By “homolog” is meant apolypeptide having at least about 35%, usually at least about 40% andmore usually at least about 60% amino acid sequence identity to aparticular differentially expressed protein as identified above, wheresequence identity is determined using the BLAST 2.0 algorithm, with theparameters described supra.

In general, the polypeptides of interest in the subject invention areprovided in a non-naturally occurring environment, e.g. are separatedfrom their naturally occurring environment. In certain embodiments, thesubject protein is present in a composition that is enriched for theprotein as compared to a cell or extract of a cell that naturallyproduces the protein. As such, isolated polypeptide is provided, whereby “isolated” or “in substantially isolated form” is meant that theprotein is present in a composition that is substantially free of otherpolypeptides, where by substantially free is meant that less than 90%,usually less than 60% and more usually less than 50% of the compositionis made up of other polypeptides of a cell that the protein is naturallyfound.

Also within the scope of the invention are variants; variants ofpolypeptides include mutants, fragments, and fusions. Mutants caninclude amino acid substitutions, additions or deletions. The amino acidsubstitutions can be conservative amino acid substitutions orsubstitutions to eliminate non-essential amino acids, such as to alter aglycosylation site, a phosphorylation site or an acetylation site, or tominimize misfolding by substitution or deletion of one or more cysteineresidues that are not necessary for function. Conservative amino acidsubstitutions are those that preserve the general charge,hydrophobicity/hydrophilicity, and/or steric bulk of the amino acidsubstituted.

Variants can be designed so as to retain or have enhanced biologicalactivity of a particular region of the protein (e.g., a functionaldomain and/or, where the polypeptide is a member of a protein family, aregion associated with a consensus sequence). For example, muteins canbe made which are optimized for increased antigenicity, i.e. amino acidvariants of a polypeptide may be made that increase the antigenicity ofthe polypeptide. Selection of amino acid alterations for production ofvariants can be based upon the accessibility (interior vs. exterior) ofthe amino acid (see, e.g., Go et al, Int. J. Peptide Protein Res. (1980)15:211), the thermostability of the variant polypeptide (see, e.g.,Querol et al., Prot. Eng. (1996) 9:265), desired glycosylation sites(see, e.g., Olsen and Thomsen, J. Gen. Microbiol. (1991) 137:579),desired disulfide bridges (see, e.g., Clarke et al., Biochemistry (1993)32:4322; and Wakarchuk et al., Protein Eng. (1994) 7:1379), desiredmetal binding sites (see, e.g., Toma et al., Biochemistry (1991) 30:97,and Haezerbrouck et al., Protein Eng. (1993) 6:643), and desiredsubstitutions with in proline loops (see, e.g., Masul et al., Appl. Env.Microbiol. (1994) 60:3579). Cysteine-depleted muteins can be produced asdisclosed in U.S. Pat. No. 4,959,314. Variants also include fragments ofthe polypeptides disclosed herein, particularly biologically activefragments and/or fragments corresponding to functional domains.Fragments of interest will typically be at least about 10 aa to at leastabout 15 aa in length, usually at least about 50 aa in length, and canbe as long as 300 aa in length or longer, but will usually not exceedabout 1000 aa in length, where the fragment will have a stretch of aminoacids that is identical to a polypeptide encoded by a polynucleotidehaving a sequence of any one of the polynucleotide sequences providedherein, or a homolog thereof. The protein variants described herein areencoded by polynucleotides that are within the scope of the invention.The genetic code can be used to select the appropriate codons toconstruct the corresponding variants.

A fragment of a subject polypeptide is, for example, a polypeptidehaving an amino acid sequence which is a portion of a subjectpolypeptide e.g. a polypeptide encoded by a subject polynucleotide thatis identified by any one of the sequence of SEQ ID NOS 1-499 or itscomplement. The polypeptide fragments of the invention are preferably atleast about 9 aa, at least about 15 aa, and more preferably at leastabout 20 aa, still more preferably at least about 30 aa, and even morepreferably, at least about 40 aa, at least about 50 aa, at least about75 aa, at least about 100 aa, at least about 125 aa or at least about150 aa in length. A fragment “at least 20 aa in length,” for example, isintended to include 20 or more contiguous amino acids from, for example,the polypeptide encoded by a cDNA, in a cDNA clone contained in adeposited library, or a nucleotide sequence shown in SEQ ID NOS:1-23767or the complementary stand thereof. In this context “about” includes theparticularly recited value or a value larger or smaller by several (5,4, 3, 2, or 1) amino acids. These polypeptide fragments have uses thatinclude, but are not limited to, production of antibodies as discussedherein. Of course, larger fragments (e.g., at least 150, 175, 200, 250,500, 600, 1000, or 2000 amino acids in length) are also encompassed bythe invention.

Moreover, representative examples of polypeptides fragments of theinvention (useful in, for example, as antigens for antibody production),include, for example, fragments comprising, or alternatively consistingof, a sequence from about amino acid number 1-10, 5-10, 10-20, 21-31,31-40, 41-61, 61-81, 91-120, 121-140, 141-162, 162-200, 201-240,241-280, 281-320, 321-360, 360-400, 400-450, 451-500, 500-600, 600-700,700-800, 800-900 and the like. In this context “about” includes theparticularly recited range or a range larger or smaller by several (5,4, 3, 2, or 1) amino acids, at either terminus or at both termini. Insome embodiments, these fragments has a functional activity (e.g.,biological activity) whereas in other embodiments, these fragments maybe used to make an antibody.

In one example, a polynucleotide having a sequence set forth in thesequence listing, containing no flanking sequences (i.e., consisting ofthe sequence set forth in the sequence listing), may be cloned into anexpression vector having ATG and a stop codon (e.g. any one of the pETvector from Invitrogen, or other similar vectors from othermanufactures), and used to express a polypeptide of interest encoded bythe polynucleotide in a suitable cell, e.g., a bacterial cell.Accordingly, the polynucleotides may be used to produce polypeptides,and these polypeptides may be used to produce antibodies by knownmethods described above and below. In many embodiments, the sequence ofthe encoded polypeptide does not have to be known prior to itsexpression in a cell. However, if it desirable to know the sequence ofthe polypeptide, this may be derived from the sequence of thepolynucleotide. Using the genetic code, the polynucleotide may betranslated by hand, or by computer means. Suitable software foridentifying open reading frames and translating them into polypeptidesequences are well know in the art, and include: Lasergene™ from DNAStar(Madison, Wis.), and Vector NTI™ from Informax (Frederick Md.), and thelike.

Further polypeptide variants may are described in PCT publicationsWO/00-55173, WO/01-07611 and WO/02-16429

Vectors, Host Cells and Protein Production

The present invention also relates to vectors containing thepolynucleotide of the present invention, host cells, and the productionof polypeptides by recombinant techniques. The vector may be, forexample, a phage, plasmid, viral, or retroviral vector. Retroviralvectors may be replication competent or replication defective. In thelatter case, viral propagation generally will occur only incomplementing host cells.

The polynucleotides of the invention may be joined to a vectorcontaining a selectable marker for propagation in a host. Generally, aplasmid vector is introduced in a precipitate, such as a calciumphosphate precipitate, or in a complex with a charged lipid. If thevector is a virus, it may be packaged in vitro using an appropriatepackaging cell line and then transduced into host cells.

The polynucleotide insert should be operatively linked to an appropriatepromoter, such as the phage lambda PL promoter, the E. coli lac, trp,phoA and tac promoters, the SV40 early and late promoters and promotersof retroviral LTRs, to name a few. Other suitable promoters will beknown to the skilled artisan. The expression constructs will furthercontain sites for transcription initiation, termination, and, in thetranscribed region, a ribosome binding site for translation. The codingportion of the transcripts expressed by the constructs will preferablyinclude a translation initiating codon at the beginning and atermination codon (UAA, UGA or UAG) appropriately positioned at the endof the polypeptide to be translated.

As indicated, the expression vectors will preferably include at leastone selectable marker. Such markers include dihydrofolate reductase,G418 or neomycin resistance for eukaryotic cell culture andtetracycline, kanamycin or ampicillin resistance genes for culturing inE. coli and other bacteria.

Representative examples of appropriate hosts include, but are notlimited to, bacterial cells, such as E. coli, Streptomyces andSalmonella typhimurium cells; fungal cells, such as yeast cells (e.g.,Saccharomyces cerevisiae or Pichia pastoris (ATCC Accession No.201178)); insect cells such as Drosophila S2 and Spodoptera Sf9 cells;animal cells such as CHO, COS, 293, and Bowes melanoma cells; and plantcells. 5 Appropriate culture mediums and conditions for theabove-described host cells are known in the art.

Among vectors preferred for use in bacteria include pQE70, pQE60 andpQE-9, available from QIAGEN, Inc.; pBluescript vectors, Phagescriptvectors, pNHSA, pNH16a, pNH18A, pNH46A, available from StratageneCloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRITSavailable from Pharmacia Biotech, Inc. Among preferred eukaryoticvectors are pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available fromStratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia.Preferred expression vectors for use in yeast systems include, but arenot limited to pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ,pGAPZalph, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, pPIC9K, andPAO815 (all available from Invitrogen, Carload, Calif.). Other suitablevectors will be readily apparent to the skilled artisan.

Nucleic acids of interest may be cloned into a suitable vector by routemethods. Suitable vectors include plasmids, cosmids, recombinant viralvectors e.g. retroviral vectors, YACs, BACs and the like, phage vectors.

Introduction of the construct into the host cell can be effected bycalcium phosphate transfection, DEAE-dextran mediated transfection,cationic lipid-mediated transfection, electroporation, transduction,infection, or other methods. Such methods are described in many standardlaboratory manuals, such as Davis et al., Basic Methods In MolecularBiology (1986). It is specifically contemplated that the polypeptides ofthe present invention may in fact be expressed by a host cell lacking arecombinant vector.

A polypeptide of this invention can be recovered and purified fromrecombinant cell cultures by well-known methods including ammoniumsulfate or ethanol precipitation, acid extraction, anion or cationexchange chromatography, phosphocellulose chromatography, hydrophobicinteraction chromatography, affinity chromatography, hydroxylapatitechromatography and lectin chromatography. Most preferably, highperformance liquid chromatography (“HPLC”) is employed for purification.

Polypeptides of the present invention can also be recovered from:products purified from natural sources, including bodily fluids, tissuesand cells, whether directly isolated or cultured; products of chemicalsynthetic procedures; and products produced by recombinant techniquesfrom a prokaryotic or eukaryotic host, including, for example,bacterial, yeast higher plant, insect, and mammalian cells. Dependingupon the host employed in a recombinant production procedure, thepolypeptides of the present invention may be glycosylated or may benon-glycosylated. In addition, polypeptides of the invention may alsoinclude an initial modified methionine residue, in some cases as aresult of host mediated processes. Thus, it is well known in the artthat the N-terminal methionine encoded by the translation initiationcodon generally is removed with high efficiency from any protein aftertranslation in all eukaryotic cells. While the N-terminal methionine onmost proteins also is efficiently removed in most prokaryotes, for someproteins, this prokaryotic removal process is inefficient, depending onthe nature of the amino acid to which the N-terminal methionine iscovalently linked.

Suitable methods and compositions for polypeptide expression may befound in PCT publications WO/00-55173, WO/01-07611 and WO/02-16429, andsuitable methods and compositions for production of modifiedpolypeptides may be found in PCT publications WO/00-55173, WO/01-07611and WO/02-16429.

Antibodies and Other Polypeptide or Polynucleotide Binding Molecules

The present invention further provides antibodies, which may be isolatedantibodies, that are specific for a polypeptide encoded by apolynucleotide described herein and/or a polypeptide of a gene thatcorresponds to a polynucleotide described herein. Antibodies can beprovided in a composition comprising the antibody and a buffer and/or apharmaceutically acceptable excipient. Antibodies specific for apolypeptide associated with cancer are useful in a variety of diagnosticand therapeutic methods, as discussed in detail herein.

Gene products, including polypeptides, mRNA (particularly mRNAs havingdistinct secondary and/or tertiary structures), cDNA, or complete gene,can be prepared and used for raising antibodies for experimental,diagnostic, and therapeutic purposes. Antibodies may be used to identifya gene corresponding to a polynucleotide. The polynucleotide or relatedcDNA is expressed as described above, and antibodies are prepared. Theseantibodies are specific to an epitope on the polypeptide encoded by thepolynucleotide, and can precipitate or bind to the corresponding nativeprotein in a cell or tissue preparation or in a cell-free extract of anin vitro expression system.

Antibodies

Further polypeptides of the invention relate to antibodies and T-cellantigen receptors (TCR) which immunospecifically bind a subjectpolypeptide, subject polypeptide fragment, or variant thereof, and/or anepitope thereof (as determined by immunoassays well known in the art forassaying specific antibody-antigen binding). Antibodies of the inventioninclude, but are not limited to, polyclonal, monoclonal, multispecific,human, humanized or chimeric antibodies, single chain antibodies, Fabfragments, F(ab′) fragments, fragments produced by a Fab expressionlibrary, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Idantibodies to antibodies of the invention), and epitope-bindingfragments of any of the above. The term “antibody,” as used herein,refers to immunoglobulin molecules and immunologically active portionsof immunoglobulin molecules, i.e., molecules that contain an antigenbinding site that immunospecifically binds an antigen. Theimmunoglobulin molecules of the invention can be of any type (e.g., IgG,IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1and IgA2) or subclass of immunoglobulin molecule.

Most preferably the antibodies are human antigen-binding antibodyfragments of the present invention and include, but are not limited to,Fab. Fab′ and F(ab′)₂, Fd, single-chain Fvs (scFv), single-chainantibodies, disulfide-linked Fvs (sdFv) and fragments comprising eithera V_(L) or V_(H) domain. Antigen-binding antibody fragments, includingsingle-chain antibodies, may comprise the variable region(s) alone or incombination with the entirety or a portion of the following: hingeregion, C_(H)1, C_(H)2, and C_(H)3 domains. Also included in theinvention are antigen-binding fragments also comprising any combinationof variable region(s) with a hinge region, C_(H)1, C_(H)2, and C_(H)3domains. The antibodies of the invention may be from any animal originincluding birds and mammals. Preferably, the antibodies are human,murine (e.g., mouse and rat), donkey, ship rabbit, goat, guinea pig,camel, horse, or chicken. As used herein, “human” antibodies includeantibodies having the amino acid sequence of a human immunoglobulin andinclude antibodies isolated from, human immunoglobulin libraries or fromanimals transgenic for one or more human immunoglobulin and that do notexpress endogenous immunoglobulins, as described infra and, for examplein, U.S. Pat. No. 5,939,598 by Kucherlapati et al.

The antibodies of the present invention may be monospecific, bispecific,trispecific or of greater multispecificity. Multispecific antibodies maybe specific for different epitopes of a polypeptide of the presentinvention or may be specific for both a polypeptide of the presentinvention as well as for a heterologous epitope, such as a heterologouspolypeptide or solid support material. See, e.g., PCT publications WO93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J.Immunol. 147:60-69 (1991); U.S. Pat. Nos. 4,474,893; 4,714,681;4,925,648; 5,573,920; 5,601,819; Kostelny et al., J. Immunol.148:1547-1553 (1992).

Antibodies of the present invention may be described or specified interms of the epitope(s) or portion(s) of a polypeptide of the presentinvention which they recognize or specifically bind. The epitope(s) orpolypeptide portion(s) may be specified as described herein, e.g., byN-terminal and C-terminal positions, or by size in contiguous amino acidresidues. Antibodies which specifically bind any epitope or polypeptideof the present invention may also be excluded. Therefore, the presentinvention includes antibodies that specifically bind polypeptides of thepresent invention, and allows for the exclusion of the same.

Antibodies of the present invention may also be described or specifiedin terms of their cross-reactivity. Antibodies that do not bind anyother analog, ortholog, or homolog of a polypeptide of the presentinvention are included. Antibodies that bind polypeptides with at least95%, at least 90%, at least 85%, at least 80%, at least 75%, at least70%, at least 65%, at least 60%, at least 55%, and at least 50% identity(as calculated using methods known in the art and described herein) to apolypeptide of the present invention are also included in the presentinvention. In specific embodiments, antibodies of the present inventioncross-react with murine, rat and/or rabbit homologs of human proteinsand the corresponding epitopes thereof. Antibodies that do not bindpolypeptides with less than 95%, less than 90%, less than 85%, less than80%, less than 75%, less than 70%, less than 65%, less than 60%, lessthan 55%, and less than 50% identity (as calculated using methods knownin the art and described herein) to a polypeptide of the presentinvention are also included in the present invention. In a specificembodiment, the above-described cross-reactivity is with respect to anysingle specific antigenic or immunogenic polypeptide, or combination(s)of 2, 3, 4, 5, or more of the specific antigenic and/or immunogenicpolypeptides disclosed herein. Further included in the present inventionare antibodies which bind polypeptides encoded by polynucleotides whichhybridize to a polynucleotide of the present invention under stringenthybridization conditions (as described herein). Antibodies of thepresent invention may also be described or specified in terms of theirbinding affinity to a polypeptide of the invention. Preferred bindingaffinities include those with a dissociation constant or Kd less 5×10⁻⁵M, 10⁻⁵ M, 5×10⁻⁶ M, 10⁻⁶ M, 5×10⁻⁷ M, 10⁻⁷ M, 5×10⁻⁸ M, 10⁻⁸ M, 5×10⁻⁹M, 10⁻⁹ M, 5×10⁻¹⁰ M, 10−10 M, etc.

The invention also provides antibodies that competitively inhibitbinding of an antibody to an epitope of the invention as determined byany method known in the art for determining competitive binding, forexample, the immunoassays described herein. In preferred embodiments,the antibody competitively inhibits binding to the epitope by at least95%, at least 90%, at least 85%, at least 80%, at least 75%, at least70%, at least 60%, or at least 50%.

Methods for making screening, assaying, humanizing, and modifyingdifferent types of antibody are well known in the art and may be foundin PCT publications WO/00-55173, WO/01-07611 and WO/02-16429.

In addition, the invention further provides polynucleotides comprising anucleotide sequence encoding an antibody of the invention and fragmentsthereof. The invention also encompasses polynucleotides that hybridizeunder stringent or alternatively, under lower stringency hybridizationconditions, e.g., as defined supra, to polynucleotides that encode anantibody, preferably, that specifically binds to a polypeptide of theinvention, preferably, an antibody that binds to a subject polypeptide.

The antibodies of the invention can be produced by any method known inthe art for the synthesis of antibodies, in particular, by chemicalsynthesis or preferably, by recombinant expression techniques.Recombinant expression of an antibody of the invention, or fragment,derivative or analog thereof, (e.g., a heavy or light chain of anantibody of the invention or a single chain antibody of the invention),requires construction of an expression vector containing apolynucleotide that encodes the antibody. Once a polynucleotide encodingan antibody molecule or a heavy or light chain of an antibody, orportion thereof (preferably containing the heavy or light chain variabledomain), of the invention has been obtained, the vector for theproduction of the antibody molecule may be produced by recombinant DNAtechnology using techniques well known in the art. Thus, methods forpreparing a protein by expressing a polynucleotide containing anantibody encoding nucleotide sequence are described herein. Methodswhich are well known to those skilled in the art can be used toconstruct expression vectors containing antibody coding sequences andappropriate transcriptional and translational control signals. Thesemethods include, for example, in vitro recombinant DNA techniques,synthetic techniques, and in vivo genetic recombination. The invention,thus, provides replicable vectors comprising a nucleotide sequenceencoding an antibody molecule of the invention, or a heavy or lightchain thereof, or a heavy or light chain variable domain, operablylinked to a promoter. Such vectors may include the nucleotide sequenceencoding the constant region of the antibody molecule (see, e.g., PCTPublication WO 86/05807; PCT Publication WO 89/01036; and U.S. Pat. No.5,122,464) and the variable domain of the antibody may be cloned intosuch a vector for expression of the entire heavy or light chain.

The expression vector is transferred to a host cell by conventionaltechniques and the transfected cells are then cultured by conventionaltechniques to produce an antibody of the invention. Thus, the inventionincludes host cells containing a polynucleotide encoding an antibody ofthe invention, or a heavy or light chain thereof, or a single chainantibody of the invention, operably linked to a heterologous promoter.In preferred embodiments for the expression of double-chainedantibodies, vectors encoding both the heavy and light chains may beco-expressed in the host cell for expression of the entireimmunoglobulin molecule, as detailed below.

A variety of host-expression vector systems may be utilized to expressthe antibody molecules of the invention. Such host-expression systemsrepresent vehicles by which the coding sequences of interest may beproduced and subsequently purified, but also represent cells which may,when transformed or transfected with the appropriate nucleotide codingsequences, express an antibody molecule of the invention in situ. Theseinclude but are not limited to microorganisms such as bacteria (e.g., E.coli, B. subtilis) transformed with recombinant bacteriophage DNA,plasmid DNA or cosmid DNA expression vectors containing antibody codingsequences; yeast (e.g., Saccharomyces, Pichia) transformed withrecombinant yeast expression vectors containing antibody codingsequences; insect cell systems infected with recombinant virusexpression vectors (e.g., baculovirus) containing antibody codingsequences; plant cell systems infected with recombinant virus expressionvectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus,TMV) or transformed with recombinant plasmid expression vectors (e.g.,Ti plasmid) containing antibody coding sequences; or mammalian cellsystems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinantexpression constructs containing promoters derived from the genome ofmammalian cells (e.g., metallothionein promoter) or from mammalianviruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5Kpromoter). Preferably, bacterial cells such as Escherichia coli, andmore preferably, eukaryotic cells, especially for the expression ofwhole recombinant antibody molecule, are used for the expression of arecombinant antibody molecule. For example, mammalian cells such asChinese hamster ovary cells (CHO), in conjunction with a vector such asthe major intermediate early gene promoter element from humancytomegalovirus is an effective expression system for antibodies(Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2(1990)).

Antibodies production is well known in the art. Exemplary methods andcompositions for making antibodies may be found in PCT publicationsWO/00-55173, WO/01-07611 and WO/02-16429.

Immunophenotyping

The antibodies of the invention may be utilized for immunophenotyping ofcell lines and biological samples. The translation product of the geneof the present invention may be useful as a cell specific marker, ormore specifically as a cellular marker that is differentially expressedat various stages of differentiation and/or maturation of particularcell types. Monoclonal antibodies directed against a specific epitope,or combination of epitopes, will allow for the screening of cellularpopulations expressing the marker. Various techniques can be utilizedusing monoclonal antibodies to screen for cellular populationsexpressing the marker(s), and include magnetic separation usingantibody-coated magnetic beads, “panning” with antibody attached to asolid matrix (i.e., plate), and flow cytometry (See, e.g., U.S. Pat. No.5,985,660; and Morrison et al. Cell, 96:737-49 (1999)).

These techniques allow for the screening of particular populations ofcells, such as might be found with hematological malignancies (i.e.minimal residual disease (MRD) in acute leukemic patients) and “non-selfcells in transplantations to prevent Graft-versus-Host Disease (GVHD).Alternatively, these techniques allow for the screening of hematopoieticstem and progenitor cells capable of undergoing proliferation and/ordifferentiation, as might be found in human umbilical cord blood.

Kits

Also provided by the subject invention are kits for practicing thesubject methods, as described above. The subject kits include at leastone or more of: a subject nucleic acid, isolated polypeptide or anantibody thereto. Other optional components of the kit include:restriction enzymes, control primers and plasmids; buffers, cells,carriers adjuvents etc. The nucleic acids of the kit may also haverestrictions sites, multiple cloning sites, primer sites, etc tofacilitate their ligation other plasmids. The various components of thekit may be present in separate containers or certain compatiblecomponents may be precombined into a single container, as desired. Inmany embodiments, kits with unit doses of the active agent, e.g. in oralor injectable doses, are provided. In certain embodiments, controls,such as samples from a cancerous or non-cancerous cell are provided bythe invention. Further embodiments of the kit include an antibody for asubject polypeptide and a chemotherapeutic agent to be used incombination with the polypeptide as a treatment.

In addition to above-mentioned components, the subject kits typicallyfurther include instructions for using the components of the kit topractice the subject methods. The instructions for practicing thesubject methods are generally recorded on a suitable recording medium.For example, the instructions may be printed on a substrate, such aspaper or plastic, etc. As such, the instructions may be present in thekits as a package insert, in the labeling of the container of the kit orcomponents thereof (i.e., associated with the packaging or subpackaging)etc. In other embodiments, the instructions are present as an electronicstorage data file present on a suitable computer readable storagemedium, e.g. CD-ROM, diskette, etc. In yet other embodiments, the actualinstructions are not present in the kit, but means for obtaining theinstructions from a remote source, e.g. via the internet, are provided.An example of this embodiment is a kit that includes a web address wherethe instructions can be viewed and/or from which the instructions can bedownloaded. As with the instructions, this means for obtaining theinstructions is recorded on a suitable substrate.

Computer-Related Embodiments

In general, a library of polynucleotides is a collection of sequenceinformation, which information is provided in either biochemical form(e.g., as a collection of polynucleotide molecules), or in electronicform (e.g., as a collection of polynucleotide sequences stored in acomputer-readable form, as in a computer system and/or as part of acomputer program). The sequence information of the polynucleotides canbe used in a variety of ways, e.g., as a resource for gene discovery, asa representation of sequences expressed in a selected cell type (e.g.,cell type markers), and/or as markers of a given disease or diseasestate. For example, in the instant case, the sequences ofpolynucleotides and polypeptides corresponding to genes differentiallyexpressed in cancer, as well as the nucleic acid and amino acidsequences of the genes themselves, can be provided in electronic form ina computer database.

In general, a disease marker is a representation of a gene product thatis present in all cells affected by disease either at an increased ordecreased level relative to a normal cell (e.g., a cell of the same orsimilar type that is not substantially affected by disease). Forexample, a polynucleotide sequence in a library can be a polynucleotidethat represents an mRNA, polypeptide, or other gene product encoded bythe polynucleotide, that is either overexpressed or underexpressed in acancerous cell affected by cancer relative to a normal (i.e.,substantially disease-free) cell.

The nucleotide sequence information of the library can be embodied inany suitable form, e.g., electronic or biochemical forms. For example, alibrary of sequence information embodied in electronic form comprises anaccessible computer data file (or, in biochemical form, a collection ofnucleic acid molecules) that contains the representative nucleotidesequences of genes that are differentially expressed (e.g.,overexpressed or underexpressed) as between, for example, i) a cancerouscell and a normal cell; ii) a cancerous cell and a dysplastic cell; iii)a cancerous cell and a cell affected by a disease or condition otherthan cancer; iv) a metastatic cancerous cell and a normal cell and/ornon-metastatic cancerous cell; v) a malignant cancerous cell and anon-malignant cancerous cell (or a normal cell) and/or vi) a dysplasticcell relative to a normal cell. Other combinations and comparisons ofcells affected by various diseases or stages of disease will be readilyapparent to the ordinarily skilled artisan. Biochemical embodiments ofthe library include a collection of nucleic acids that have thesequences of the genes in the library, where the nucleic acids cancorrespond to the entire gene in the library or to a fragment thereof,as described in greater detail below.

The polynucleotide libraries of the subject invention generally comprisesequence information of a plurality of polynucleotide sequences, whereat least one of the polynucleotides has a sequence of any of sequencedescribed herein. By plurality is meant at least 2, usually at least 3and can include up to all of the sequences described herein. The lengthand number of polynucleotides in the library will vary with the natureof the library, e.g., if the library is an oligonucleotide array, a cDNAarray, a computer database of the sequence information, etc.

Where the library is an electronic library, the nucleic acid sequenceinformation can be present in a variety of media. “Media” refers to amanufacture, other than an isolated nucleic acid molecule, that containsthe sequence information of the present invention. Such a manufactureprovides the genome sequence or a subset thereof in a form that can beexamined by means not directly applicable to the sequence as it existsin a nucleic acid. For example, the nucleotide sequence of the presentinvention, e.g. the nucleic acid sequences of any of the polynucleotidesof the sequences described herein, can be recorded on computer readablemedia, e.g. any medium that can be read and accessed directly by acomputer. Such media include, but are not limited to: magnetic storagemedia, such as a floppy disc, a hard disc storage medium, and a magnetictape; optical storage media such as CD-ROM; electrical storage mediasuch as RAM and ROM; and hybrids of these categories such asmagnetic/optical storage media.

One of skill in the art can readily appreciate how any of the presentlyknown computer readable mediums can be used to create a manufacturecomprising a recording of the present sequence information. “Recorded”refers to a process for storing information on computer readable medium,using any such methods as known in the art. Any convenient data storagestructure can be chosen, based on the means used to access the storedinformation. A variety of data processor programs and formats can beused for storage, e.g. word processing text file, database format, etc.In addition to the sequence information, electronic versions oflibraries comprising one or more sequence described herein can beprovided in conjunction or connection with other computer-readableinformation and/or other types of computer-readable files (e.g.,searchable files, executable files, etc, including, but not limited to,for example, search program software, etc.).

By providing the nucleotide sequence in computer readable form, theinformation can be accessed for a variety of purposes. Computer softwareto access sequence information (e.g. the NCBI sequence database) ispublicly available. For example, the gapped BLAST (Altschul et al.,Nucleic Acids Res. (1997) 25:3389-3402) and BLAZE (Brutlag et al., Comp.Chem. (1993) 17:203) search algorithms on a Sybase system, or theTeraBLAST (TimeLogic, Crystal Bay, Nev.) program optionally running on aspecialized computer platform available from TimeLogic, can be used toidentify open reading frames (ORFs) within the genome that containhomology to ORFs from other organisms.

As used herein, “a computer-based system” refers to the hardware means,software means, and data storage means used to analyze the nucleotidesequence information of the present invention. The minimum hardware ofthe computer-based systems of the present invention comprises a centralprocessing unit (CPU), input means, output means, and data storagemeans. A skilled artisan can readily appreciate that any one of thecurrently available computer-based system are suitable for use in thepresent invention. The data storage means can comprise any manufacturecomprising a recording of the present sequence information as describedabove, or a memory access means that can access such a manufacture.

“Search means” refers to one or more programs implemented on thecomputer-based system, to compare a target sequence or target structuralmotif, or expression levels of a polynucleotide in a sample, with thestored sequence information. Search means can be used to identifyfragments or regions of the genome that match a particular targetsequence or target motif. A variety of known algorithms are publiclyknown and commercially available, e.g. MacPattern (EMBL), TeraBLAST(TimeLogic), BLASTN and BLASTX (NCBI). A “target sequence” can be anypolynucleotide or amino acid sequence of six or more contiguousnucleotides or two or more amino acids, preferably from about 10 to 100amino acids or from about 30 to 300 nt. A variety of means for comparingnucleic acids or polypeptides may be used to compare accomplish asequence comparison (e.g., to analyze target sequences, target motifs,or relative expression levels) with the data storage means. A skilledartisan can readily recognize that any one of the publicly availablehomology search programs can be used to search the computer basedsystems of the present invention to compare of target sequences andmotifs. Computer programs to analyze expression levels in a sample andin controls are also known in the art.

A “target structural motif,” or “target motif,” refers to any rationallyselected sequence or combination of sequences in which the sequence(s)are chosen based on a three-dimensional configuration that is formedupon the folding of the target motif, or on consensus sequences ofregulatory or active sites. There are a variety of target motifs knownin the art. Protein target motifs include, but are not limited to,enzyme active sites and signal sequences, kinase domains, receptorbinding domains, SH2 domains, SH3 domains, phosphorylation sites,protein interaction domains, transmembrane domains, etc. Nucleic acidtarget motifs include, but are not limited to, hairpin structures,promoter sequences and other expression elements such as binding sitesfor transcription factors.

A variety of structural formats for the input and output means can beused to input and output the information in the computer-based systemsof the present invention. One format for an output means ranks therelative expression levels of different polynucleotides. Suchpresentation provides a skilled artisan with a ranking of relativeexpression levels to determine a gene expression profile. A geneexpression profile can be generated from, for example, a cDNA libraryprepared from mRNA isolated from a test cell suspected of beingcancerous or pre-cancerous, comparing the sequences or partial sequencesof the clones against the sequences in an electronic database, where thesequences of the electronic database represent genes differentiallyexpressed in a cancerous cell, e.g., a cancerous breast cell. The numberof clones having a sequence that has substantial similarity to asequence that represents a gene differentially expressed in a cancerouscell is then determined, and the number of clones corresponding to eachof such genes is determined. An increased number of clones thatcorrespond to differentially expressed gene is present in the cDNAlibrary of the test cell (relative to, for example, the number of clonesexpected in a cDNA of a normal cell) indicates that the test cell iscancerous.

As discussed above, the “library” as used herein also encompassesbiochemical libraries of the polynucleotides of the sequences describedherein, e.g., collections of nucleic acids representing the providedpolynucleotides. The biochemical libraries can take a variety of forms,e.g., a solution of cDNAs, a pattern of probe nucleic acids stablyassociated with a surface of a solid support (i.e., an array) and thelike. Of particular interest are nucleic acid arrays in which one ormore of the genes described herein is represented by a sequence on thearray. By array is meant an article of manufacture that has at least asubstrate with at least two distinct nucleic acid targets on one of itssurfaces, where the number of distinct nucleic acids can be considerablyhigher, typically being at least 10 nt, usually at least 20 nt and oftenat least 25 nt. A variety of different array formats have been developedand are known to those of skill in the art. The arrays of the subjectinvention find use in a variety of applications, including geneexpression analysis, drug screening, mutation analysis and the like, asdisclosed in the above-listed exemplary patent documents.

In addition to the above nucleic acid libraries, analogous libraries ofpolypeptides are also provided, where the polypeptides of the librarywill represent at least a portion of the polypeptides encoded by a genecorresponding to a sequence described herein.

Diagnostic and Other Methods Involving Detection of DifferentiallyExpressed Genes

The present invention provides methods of using the polynucleotidesdescribed herein in, for example, diagnosis of cancer and classificationof cancer cells according to expression profiles. In specificnon-limiting embodiments, the methods are useful for detecting cancercells, facilitating diagnosis of cancer and the severity of a cancer(e.g., tumor grade, tumor burden, and the like) in a subject,facilitating a determination of the prognosis of a subject, andassessing the responsiveness of the subject to therapy (e.g., byproviding a measure of therapeutic effect through, for example,assessing tumor burden during or following a chemotherapeutic regimen).Detection can be based on detection of a polynucleotide that isdifferentially expressed in a cancer cell, and/or detection of apolypeptide encoded by a polynucleotide that is differentially expressedin a cancer cell (“a polypeptide associated with cancer”). The detectionmethods of the invention can be conducted in vitro or in vivo, onisolated cells, or in whole tissues or a bodily fluid, e.g., blood,plasma, serum, urine, and the like).

In general, methods of the invention involving detection of a geneproduct (e.g., mRNA, cDNA generated from such mRNA, and polypeptides)involve contacting a sample with a probe specific for the gene productof interest. “Probe” as used herein in such methods is meant to refer toa molecule that specifically binds a gene product of interest (e.g., theprobe binds to the target gene product with a specificity sufficient todistinguish binding to target over non-specific binding to non-target(background) molecules). “Probes” include, but are not necessarilylimited to, nucleic acid probes (e.g., DNA, RNA, modified nucleic acid,and the like), antibodies (e.g., antibodies, antibody fragments thatretain binding to a target epitope, single chain antibodies, and thelike), or other polypeptide, peptide, or molecule (e.g., receptorligand) that specifically binds a target gene product of interest.

The probe and sample suspected of having the gene product of interestare contacted under conditions suitable for binding of the probe to thegene product. For example, contacting is generally for a time sufficientto allow binding of the probe to the gene product (e.g. from severalminutes to a few hours), and at a temperature and conditions ofosmolarity and the like that provide for binding of the probe to thegene product at a level that is sufficiently distinguishable frombackground binding of the probe (e.g., under conditions that minimizenon-specific binding). Suitable conditions for probe-target gene productbinding can be readily determined using controls and other techniquesavailable and known to one of ordinary skill in the art.

In this embodiment, the probe can be an antibody or other polypeptide,peptide, or molecule (e.g., receptor ligand) that specifically binds atarget polypeptide of interest.

The detection methods can be provided as part of a kit. Thus, theinvention further provides kits for detecting the presence and/or alevel of a polynucleotide that is differentially expressed in a cancercell (e.g., by detection of an mRNA encoded by the differentiallyexpressed gene of interest), and/or a polypeptide encoded thereby, in abiological sample. Procedures using these kits can be performed byclinical laboratories, experimental laboratories, medical practitioners,or private individuals. The kits of the invention for detecting apolypeptide encoded by a polynucleotide that is differentially expressedin a cancer cell comprise a moiety that specifically binds thepolypeptide, which may be a specific antibody. The kits of the inventionfor detecting a polynucleotide that is differentially expressed in acancer cell comprise a moiety that specifically hybridizes to such apolynucleotide. The kit may optionally provide additional componentsthat are useful in the procedure, including, but not limited to,buffers, developing reagents, labels, reacting surfaces, means fordetection, control samples, standards, instructions, and interpretiveinformation.

Detecting a Polypeptide Encoded by a Polynucleotide that isDifferentially Expressed in a Cancer Cell

In some embodiments, methods are provided for a detecting cancer cell bydetecting in a cell, a polypeptide encoded by a gene differentiallyexpressed in a cancer cell. Any of a variety of known methods can beused for detection, including, but not limited to, immunoassay, using anantibody specific for the encoded polypeptide, e.g., by enzyme-linkedimmunosorbent assay (ELISA), radioimmunoassay (RIA), and the like; andfunctional assays for the encoded polypeptide, e.g., binding activity orenzymatic activity.

For example, an immunofluorescence assay can be easily performed oncells without first isolating the encoded polypeptide. The cells arefirst fixed onto a solid support, such as a microscope slide ormicrotiter well. This fixing step can permeabilize the cell membrane.The permeablization of the cell membrane permits thepolypeptide-specific probe (e.g, antibody) to bind. Alternatively, wherethe polypeptide is secreted or membrane-bound, or is otherwiseaccessible at the cell-surface (e.g., receptors, and other moleculestably-associated with the outer cell membrane or otherwise stablyassociated with the cell membrane, such permeabilization may not benecessary.

Next, the fixed cells are exposed to an antibody specific for theencoded polypeptide. To increase the sensitivity of the assay, the fixedcells may be further exposed to a second antibody, which is labeled andbinds to the first antibody, which is specific for the encodedpolypeptide. Typically, the secondary antibody is detectably labeled,e.g., with a fluorescent marker. The cells which express the encodedpolypeptide will be fluorescently labeled and easily visualized underthe microscope. See, for example, Hashido et al. (1992) Biochem.Biophys. Res. Comm. 187:1241-1248.

As will be readily apparent to the ordinarily skilled artisan uponreading the present specification, the detection methods and othermethods described herein can be varied. Such variations are within theintended scope of the invention. For example, in the above detectionscheme, the probe for use in detection can be immobilized on a solidsupport, and the test sample contacted with the immobilized probe.Binding of the test sample to the probe can then be detected in avariety of ways, e.g., by detecting a detectable label bound to the testsample.

The present invention further provides methods for detecting thepresence of and/or measuring a level of a polypeptide in a biologicalsample, which polypeptide is encoded by a polynucleotide that representsa gene differentially expressed in cancer, particularly in apolynucleotide that represents a gene differentially cancer cell, usinga probe specific for the encoded polypeptide. In this embodiment, theprobe can be a an antibody or other polypeptide, peptide, or molecule(e.g., receptor ligand) that specifically binds a target polypeptide ofinterest.

The methods generally comprise: a) contacting the sample with anantibody specific for a differentially expressed polypeptide in a testcell; and b) detecting binding between the antibody and molecules of thesample. The level of antibody binding (either qualitative orquantitative) indicates the cancerous state of the cell. For example,where the differentially expressed gene is increased in cancerous cells,detection of an increased level of antibody binding to the test samplerelative to antibody binding level associated with a normal cellindicates that the test cell is cancerous.

Suitable controls include a sample known not to contain the encodedpolypeptide; and a sample contacted with an antibody not specific forthe encoded polypeptide, e.g., an anti-idiotype antibody. A variety ofmethods to detect specific antibody-antigen interactions are known inthe art and can be used in the method, including, but not limited to,standard immunohistological methods, immunoprecipitation, an enzymeimmunoassay, and a radioimmunoassay.

In general, the specific antibody will be detectably labeled, eitherdirectly or indirectly. Direct labels include radioisotopes; enzymeswhose products are detectable (e.g., luciferase, β-galactosidase, andthe like); fluorescent labels (e.g., fluorescein isothiocyanate,rhodamine, phycoerythrin, and the like); fluorescence emitting metals,e.g., ¹⁵²Eu, or others of the lanthanide series, attached to theantibody through metal chelating groups such as EDTA; chemiluminescentcompounds, e.g., luminol, isoluminol, acridinium salts, and the like;bioluminescent compounds, e.g., luciferin, aequorin (green fluorescentprotein), and the like.

The antibody may be attached (coupled) to an insoluble support, such asa polystyrene plate or a bead. Indirect labels include second antibodiesspecific for antibodies specific for the encoded polypeptide (“firstspecific antibody”), wherein the second antibody is labeled as describedabove; and members of specific binding pairs, e.g., biotin-avidin, andthe like. The biological sample may be brought into contact with andimmobilized on a solid support or carrier, such as nitrocellulose, thatis capable of immobilizing cells, cell particles, or soluble proteins.The support may then be washed with suitable buffers, followed bycontacting with a detectably-labeled first specific antibody. Detectionmethods are known in the art and will be chosen as appropriate to thesignal emitted by the detectable label. Detection is generallyaccomplished in comparison to suitable controls, and to appropriatestandards.

In some embodiments, the methods are adapted for use in vivo, e.g., tolocate or identify sites where cancer cells are present. In theseembodiments, a detectably-labeled moiety, e.g., an antibody, which isspecific for a cancer-associated polypeptide is administered to anindividual (e.g., by injection), and labeled cells are located usingstandard imaging techniques, including, but not limited to, magneticresonance imaging, computed tomography scanning, and the like. In thismanner, cancer cells are differentially labeled.

Detecting a Polynucleotide that Represents a Gene DifferentiallyExpressed in a Cancer Cell

In some embodiments, methods are provided for detecting a cancer cell bydetecting expression in the cell of a transcript or that isdifferentially expressed in a cancer cell. Any of a variety of knownmethods can be used for detection, including, but not limited to,detection of a transcript by hybridization with a polynucleotide thathybridizes to a polynucleotide that is differentially expressed in acancer cell; detection of a transcript by a polymerase chain reactionusing specific oligonucleotide primers; in situ hybridization of a cellusing as a probe a polynucleotide that hybridizes to a gene that isdifferentially expressed in a cancer cell and the like.

In many embodiments, the levels of a subject gene product are measured.By measured is meant qualitatively or quantitatively estimating thelevel of the gene product in a first biological sample either directly(e.g. by determining or estimating absolute levels of gene product) orrelatively by comparing the levels to a second control biologicalsample. In many embodiments the second control biological sample isobtained from an individual not having not having cancer. As will beappreciated in the art, once a standard control level of gene expressionis known, it can be used repeatedly as a standard for comparison. Othercontrol samples include samples of cancerous tissue.

The methods can be used to detect and/or measure mRNA levels of a genethat is differentially expressed in a cancer cell. In some embodiments,the methods comprise: a) contacting a sample with a polynucleotide thatcorresponds to a differentially expressed gene described herein underconditions that allow hybridization; and b) detecting hybridization, ifany. Detection of differential hybridization, when compared to asuitable control, is an indication of the presence in the sample of apolynucleotide that is differentially expressed in a cancer cell.Appropriate controls include, for example, a sample that is known not tocontain a polynucleotide that is differentially expressed in a cancercell. Conditions that allow hybridization are known in the art, and havebeen described in more detail above.

Detection can also be accomplished by any known method, including, butnot limited to, in situ hybridization, PCR (polymerase chain reaction),RT-PCR (reverse transcription-PCR), and “Northern” or RNA blotting,arrays, microarrays, etc, or combinations of such techniques, using asuitably labeled polynucleotide. A variety of labels and labelingmethods for polynucleotides are known in the art and can be used in theassay methods of the invention. Specific hybridization can be determinedby comparison to appropriate controls.

Polynucleotides described herein are used for a variety of purposes,such as probes for detection of and/or measurement of, transcriptionlevels of a polynucleotide that is differentially expressed in a cancercell. Additional disclosure about preferred regions of the disclosedpolynucleotide sequences is found in the Examples. A probe thathybridizes specifically to a polynucleotide disclosed herein shouldprovide a detection signal at least 2-, 5-, 10-, or 20-fold higher thanthe background hybridization provided with other unrelated sequences. Itshould be noted that “probe” as used in this context of detection ofnucleic acid is meant to refer to a polynucleotide sequence used todetect a differentially expressed gene product in a test sample. As willbe readily appreciated by the ordinarily skilled artisan, the probe canbe detectably labeled and contacted with, for example, an arraycomprising immobilized polynucleotides obtained from a test sample(e.g., mRNA). Alternatively, the probe can be immobilized on an arrayand the test sample detectably labeled. These and other variations ofthe methods of the invention are well within the skill in the art andare within the scope of the invention.

Labeled nucleic acid probes may be used to detect expression of a genecorresponding to the provided polynucleotide. In Northern blots, mRNA isseparated electrophoretically and contacted with a probe. A probe isdetected as hybridizing to an mRNA species of a particular size. Theamount of hybridization can be quantitated to determine relative amountsof expression, for example under a particular condition. Probes are usedfor in situ hybridization to cells to detect expression. Probes can alsobe used in vivo for diagnostic detection of hybridizing sequences.Probes are typically labeled with a radioactive isotope. Other types ofdetectable labels can be used such as chromophores, fluorophores, andenzymes. Other examples of nucleotide hybridization assays are describedin WO92/02526 and U.S. Pat. No. 5,124,246.

PCR is another means for detecting small amounts of target nucleicacids, methods for which may be found in Sambrook, et al. MolecularCloning: A Laboratory Manual, CSH Press 1989, pp. 14.2-14.33.

A detectable label may be included in the amplification reaction.Suitable detectable labels include fluorochromes, (e.g. fluoresceinisothiocyanate (FITC), rhodamine, Texas Red, phycoerythrin,allophycocyanin, 6-carboxyfluorescein (6-FAM),2′,7′-dimethoxy-4′,5′-dichloro-6-carboxyfluorescein,6-carboxy-X-rhodamine (ROX),6-carboxy-2′,4′,7′,4,7-hexachlorofluorescein (HEX), 5-carboxyfluorescein(5-FAM) or N,N,N′,N′-tetramethyl-6-carboxyrhodamine (TAMRA)),radioactive labels, (e.g. ³²P, ³⁵S, ³H, etc.), and the like. The labelmay be a two stage system, where the polynucleotides is conjugated tobiotin, haptens, etc. having a high affinity binding partner, e.g.avidin, specific antibodies, etc., where the binding partner isconjugated to a detectable label. The label may be conjugated to one orboth of the primers. Alternatively, the pool of nucleotides used in theamplification is labeled, so as to incorporate the label into theamplification product.

Arrays

Polynucleotide arrays provide a high throughput technique that can assaya large number of polynucleotides or polypeptides in a sample. Thistechnology can be used asia tool to test for differential expression.

A variety of methods of producing arrays, as well as variations of thesemethods, are known in the art and contemplated for use in the invention.For example, arrays can be created by spotting polynucleotide probesonto a substrate (e.g., glass, nitrocellulose, etc.) in atwo-dimensional matrix or array having bound probes. The probes can bebound to the substrate by either covalent bonds or by non-specificinteractions, such as hydrophobic interactions.

Samples of polynucleotides can be detectably labeled (e.g., usingradioactive or fluorescent labels) and then hybridized to the probes.Double stranded polynucleotides, comprising the labeled samplepolynucleotides bound to probe polynucleotides, can be detected once theunbound portion of the sample is washed away. Alternatively, thepolynucleotides of the test sample can be immobilized on the array, andthe probes detectably labeled. Techniques for constructing arrays andmethods of using these arrays are described in, for example, Schena etal. (1996) Proc Natl Acad Sci USA. 93(20):10614-9; Schena et al. (1995)Science 270(5235):467-70; Shalon et al. (1996) Genome Res. 6(7):639-45,U.S. Pat. No. 5,807,522, EP 799 897; WO 97/29212; WO 97/27317; EP 785280; WO 97/02357; U.S. Pat. No. 5,593,839; U.S. Pat. No. 5,578,832; EP728 520; U.S. Pat. No. 5,599,695; EP 721 016; U.S. Pat. No. 5,556,752;WO 95/22058; and U.S. Pat. No. 5,631,734. In most embodiments, the“probe” is detectably labeled. In other embodiments, the probe isimmobilized on the array and not detectably labeled.

Arrays can be used, for example, to examine differential expression ofgenes and can be used to determine gene function. For example, arrayscan be used to detect differential expression of a gene corresponding toa polynucleotide described herein, where expression is compared betweena test cell and control cell (e.g., cancer cells and normal cells). Forexample, high expression of a particular message in a cancer cell, whichis not observed in a corresponding normal cell, can indicate a cancerspecific gene product. Exemplary uses of arrays are further describedin, for example, Pappalarado et al., Sem. Radiation Oncol. (1998) 8:217;and Ramsay, Nature Biotechnol. (1998) 16:40. Furthermore, manyvariations on methods of detection using arrays are well within theskill in the art and within the scope of the present invention. Forexample, rather than immobilizing the probe to a solid support, the testsample can be immobilized on a solid support which is then contactedwith the probe.

Diagnosis, Prognosis, Assessment of Therapy (Therametrics), andManagement of Cancer

The polynucleotides described herein, as well as their gene products andcorresponding genes and gene products, are of particular interest asgenetic or biochemical markers (e.g., in blood or tissues) that willdetect the earliest changes along the carcinogenesis pathway and/or tomonitor the efficacy of various therapies and preventive interventions.

For example, the level of expression of certain polynucleotides can beindicative of a poorer prognosis, and therefore warrant more aggressivechemo- or radio-therapy for a patient or vice versa. The correlation ofnovel surrogate tumor specific features with response to treatment andoutcome in patients can define prognostic indicators that allow thedesign of tailored therapy based on the molecular profile of the tumor.These therapies include antibody targeting, antagonists (e.g., smallmolecules), and gene therapy.

Determining expression of certain polynucleotides and comparison of apatient's profile with known expression in normal tissue and variants ofthe disease allows a determination of the best possible treatment for apatient, both in terms of specificity of treatment and in terms ofcomfort level of the patient. Surrogate tumor markers, such aspolynucleotide expression, can also be used to better classify, and thusdiagnose and treat, different forms and disease states of cancer. Twoclassifications widely used in oncology that can benefit fromidentification of the expression levels of the genes corresponding tothe polynucleotides described herein are staging of the cancerousdisorder, and grading the nature of the cancerous tissue.

The polynucleotides that correspond to differentially expressed genes,as well as their encoded-gene products, can be useful to monitorpatients having or susceptible to cancer to detect potentially malignantevents at a molecular level before they are detectable at a grossmorphological level. In addition, the polynucleotides described herein,as well as the genes corresponding to such polynucleotides, can beuseful as therametrics, e.g., to assess the effectiveness of therapy byusing the polynucleotides or their encoded gene products, to assess, forexample, tumor burden in the patient before, during, and after therapy.

Furthermore, a polynucleotide identified as corresponding to a gene thatis differentially expressed in, and thus is important for, one type ofcancer can also have implications for development or risk of developmentof other types of cancer, e.g., where a polynucleotide represents a genedifferentially expressed across various cancer types. Thus, for example,expression of a polynucleotide corresponding to a gene that has clinicalimplications for cancer can also have clinical implications formetastatic breast cancer, colon cancer, or ovarian cancer, etc.

Staging. Staging is a process used by physicians to describe howadvanced the cancerous state is in a patient. Staging assists thephysician in determining a prognosis, planning treatment and evaluatingthe results of such treatment. Staging systems vary with the types ofcancer, but generally involve the following “TNM” system: the type oftumor, indicated by T; whether the cancer has metastasized to nearbylymph nodes, indicated by N; and whether the cancer has metastasized tomore distant parts of the body, indicated by M. Generally, if a canceris only detectable in the area of the primary lesion without havingspread to any lymph nodes it is called Stage I. If it has spread only tothe closest lymph nodes, it is called Stage II. In Stage III, the cancerhas generally spread to the lymph nodes in near proximity to the site ofthe primary lesion. Cancers that have spread to a distant part of thebody, such as the liver, bone, brain or other site, are Stage IV, themost advanced stage.

The polynucleotides and corresponding genes and gene products describedherein can facilitate fine-tuning of the staging process by identifyingmarkers for the aggressiveness of a cancer, e.g. the metastaticpotential, as well as the presence in different areas of the body. Thus,a Stage II cancer with a polynucleotide signifying a high metastaticpotential cancer can be used to change a borderline Stage II tumor to aStage III tumor, justifying more aggressive therapy. Conversely, thepresence of a polynucleotide signifying a lower metastatic potentialallows more conservative staging of a tumor.

One type of breast cancer is ductal carcinoma in situ (DCIS): DCIS iswhen the breast cancer cells are completely contained within the breastducts (the channels in the breast that carry milk to the nipple), andhave not spread into the surrounding breast tissue. This may also bereferred to as non-invasive or intraductal cancer, as the cancer cellshave not yet spread into the surrounding breast tissue and so usuallyhave not spread into any other part of the body.

Lobular carcinoma in situ breast cancer (LCIS) means that cell changesare found in the lining of the lobules of the breast. It can be presentin both breasts. It is also referred to as non-invasive cancer as it hasnot spread into the surrounding breast tissue.

Invasive breast cancer can be staged as follows: Stage 1 tumours: thesemeasure less than two centimetres. The lymph glands in the armpit arenot affected and there are no signs that the cancer has spread elsewherein the body; Stage 2 tumours: these measure between two and fivecentimetres, or the lymph glands in the armpit are affected, or both.However, there are no signs that the cancer has spread further; Stage 3tumours: these are larger than five centimetres and may be attached tosurrounding structures such as the muscle or skin. The lymph glands areusually affected, but there are no signs that the cancer has spreadbeyond the breast or the lymph glands in the armpit; Stage 4 tumours:these are of any size, but the lymph glands are usually affected and thecancer has spread to other parts of the body. This is secondary breastcancer.

Grading of cancers. Grade is a term used to describe how closely a tumorresembles normal tissue of its same type. The microscopic appearance ofa tumor is used to identify tumor grade based on parameters such as cellmorphology, cellular organization, and other markers of differentiation.As a general rule, the grade of a tumor corresponds to its rate ofgrowth or aggressiveness, with undifferentiated or high-grade tumorsgenerally being more aggressive than well-differentiated or low-gradetumors.

The polynucleotides of the Sequence Listing, and their correspondinggenes and gene products, can be especially valuable in determining thegrade of the tumor, as they not only can aid in determining thedifferentiation status of the cells of a tumor, they can also identifyfactors other than differentiation that are valuable in determining theaggressiveness of a tumor, such as metastatic potential.

Low grade means that the cancer cells look very like the normal cells.They are usually slowly growing and are less likely to spread. In highgrade tumors the cells look very abnormal. They are likely to grow morequickly and are more likely to spread.

Assessment of proliferation of cells in tumor. The differentialexpression level of the polynucleotides described herein can facilitateassessment of the rate of proliferation of tumor cells, and thus providean indicator of the aggressiveness of the rate of tumor growth. Forexample, assessment of the relative expression levels of genes involvedin cell cycle can provide an indication of cellular proliferation, andthus serve as a marker of proliferation.

Detection of Cancer.

The polynucleotides corresponding to genes that exhibit the appropriateexpression pattern can be used to detect cancer in a subject. Theexpression of appropriate polynucleotides can be used in the diagnosis,prognosis and management of cancer. Detection of cancer can bedetermined using expression levels of any of these sequences alone or incombination with the levels of expression of other known cancer genes.Determination of the aggressive nature and/or the metastatic potentialof a cancer can be determined by comparing levels of one or more geneproducts of the genes corresponding to the polynucleotides describedherein, and comparing total levels of another sequence known to vary incancerous tissue, e.g., expression of p53, DCC, ras, FAP (see, e.g.,Fearon E R, et al., Cell (1990) 61(5):759; Hamilton S R et al., Cancer(1993) 72:957; Bodmer W, et al., Nat Genet. (1994) 4(3):217; Fearon E R,Ann NY Acad. Sci. (1995) 768:101). For example, development of cancercan be detected by examining the level of expression of a genecorresponding to a polynucleotides described herein to the levels ofoncogenes (e.g. ras) or tumor suppressor genes (e.g. FAP or p53). Thusexpression of specific marker polynucleotides can be used todiscriminate between normal and cancerous tissue, to discriminatebetween cancers with different cells of origin, to discriminate betweencancers with different potential metastatic rates, etc. For a review ofother markers of cancer, see, e.g., Hanahan et al. (2000) Cell100:57-70.

Treatment of Cancer

The invention further provides methods for reducing growth of cancercells. The methods provide for decreasing the expression of a gene thatis differentially expressed in a cancer cell or decreasing the level ofand/or decreasing an activity of a cancer-associated polypeptide. Ingeneral, the methods comprise contacting a cancer cell with a substancethat modulates (1) expression of a gene that is differentially expressedin cancer; or (2) a level of and/or an activity of a cancer-associatedpolypeptide.

“Reducing growth of cancer cells” includes, but is not limited to,reducing proliferation of cancer cells, and reducing the incidence of anon-cancerous cell becoming a cancerous cell. Whether a reduction incancer cell growth has been achieved can be readily determined using anyknown assay, including, but not limited to, [³H]-thymidineincorporation; counting cell number over a period of time; detectingand/or measuring a marker associated with breast cancer (e.g., PSA).

The present invention provides methods for treating cancer, generallycomprising administering to an individual in need thereof a substancethat reduces cancer cell growth, in an amount sufficient to reducecancer cell growth and treat the cancer. Whether a substance, or aspecific amount of the substance, is effective in treating cancer can beassessed using any of a variety of known diagnostic assays for cancer,including, but not limited to, proctoscopy, rectal examination, biopsy,contrast radiographic studies, CAT scan, and detection of a tumor markerassociated with cancer in the blood of the individual (e.g., PSA(breast-specific antigen)). The substance can be administeredsystemically or locally. Thus, in some embodiments, the substance isadministered locally, and cancer growth is decreased at the site ofadministration. Local administration may be useful in treating, e.g., asolid tumor.

A substance that reduces cancer cell growth can be targeted to a cancercell. Thus, in some embodiments, the invention provides a method ofdelivering a drug to a cancer cell, comprising administering adrug-antibody complex to a subject, wherein the antibody is specific fora cancer-associated polypeptide, and the drug is one that reduces cancercell growth, a variety of which are known in the art. Targeting can beaccomplished by coupling (e.g., linking, directly or via a linkermolecule, either covalently or non-covalently, so as to form adrug-antibody complex) a drug to an antibody specific for acancer-associated polypeptide. Methods of coupling a drug to an antibodyare well known in the art and need not be elaborated upon herein.

Tumor Classification and Patient Stratification

The invention further provides for methods of classifying tumors, andthus grouping or “stratifying” patients, according to the expressionprofile of selected differentially expressed genes in a tumor.Differentially expressed genes can be analyzed for correlation withother differentially expressed genes in a single tumor type or acrosstumor types. Genes that demonstrate consistent correlation in expressionprofile in a given cancer cell type (e.g., in a cancer cell or type ofcancer) can be grouped together, e.g., when one gene is overexpressed ina tumor, a second gene is also usually overexpressed. Tumors can then beclassified according to the expression profile of one or more genesselected from one or more groups.

The tumor of each patient in a pool of potential patients can beclassified as described above. Patients having similarly classifiedtumors can then be selected for participation in an investigative orclinical trial of a cancer therapeutic where a homogeneous population isdesired. The tumor classification of a patient can also be used inassessing the efficacy of a cancer therapeutic in a heterogeneouspatient population. In addition, therapy for a patient having a tumor ofa given expression profile can then be selected accordingly.

In another embodiment, differentially expressed gene products (e.g.,polypeptides or polynucleotides encoding such polypeptides) may beeffectively used in treatment through vaccination. The growth of cancercells is naturally limited in part due to immune surveillance.Stimulation of the immune system using a particular tumor-specificantigen enhances the effect towards the tumor expressing the antigen. Anactive vaccine comprising a polypeptide encoded by the cDNA of thisinvention would be appropriately administered to subjects having analteration, e.g., overabundance, of the corresponding RNA, or thosepredisposed for developing cancer cells with an alteration of the sameRNA. Polypeptide antigens are typically combined with an adjuvant aspart of a vaccine composition. The vaccine is preferably administeredfirst as a priming dose, and then again as a boosting dose, usually atleast four weeks later. Further boosting doses may be given to enhancethe effect. The dose and its timing are usually determined by the personresponsible for the treatment.

The invention also encompasses the selection of a therapeutic regimenbased upon the expression profile of differentially expressed genes inthe patient's tumor. For example, a tumor can be analyzed for itsexpression profile of the genes corresponding to SEQ ID NOS:1-23767 asdescribed herein, e.g., the tumor is analyzed to determine which genesare expressed at elevated levels or at decreased levels relative tonormal cells of the same tissue type. The expression patterns of thetumor are then compared to the expression patterns of tumors thatrespond to a selected therapy. Where the expression profiles of the testtumor cell and the expression profile of a tumor cell of known drugresponsivity at least substantially match (e.g., selected sets of genesat elevated levels in the tumor of known drug responsivity and are alsoat elevated levels in the test tumor cell), then the therapeutic agentselected for therapy is the drug to which tumors with that expressionpattern respond.

Pattern Matching in Diagnosis Using Arrays

In another embodiment, the diagnostic and/or prognostic methods of theinvention involve detection of expression of a selected set of genes ina test sample to produce a test expression pattern (TEP). The TEP iscompared to a reference expression pattern (REP), which is generated bydetection of expression of the selected set of genes in a referencesample (e.g., a positive or negative control sample). The selected setof genes includes at least one of the genes of the invention, whichgenes correspond to the polynucleotide sequences described herein. Ofparticular interest is a selected set of genes that includes genedifferentially expressed in the disease for which the test sample is tobe screened.

Identification of Therapeutic Targets and Anti-Cancer Therapeutic Agents

The present invention also encompasses methods for identification ofagents having the ability to modulate activity of a differentiallyexpressed gene product, as well as methods for identifying adifferentially expressed gene product as a therapeutic target fortreatment of cancer.

Identification of compounds that modulate activity of a differentiallyexpressed gene product can be accomplished using any of a variety ofdrug screening techniques. Such agents are candidates for development ofcancer therapies. Of particular interest are screening assays for agentsthat have tolerable toxicity for normal, non-cancerous human cells. Thescreening assays of the invention are generally based upon the abilityof the agent to modulate an activity of a differentially expressed geneproduct and/or to inhibit or suppress phenomenon associated with cancer(e.g., cell proliferation, colony formation, cell cycle arrest,metastasis, and the like).

Screening of Candidate Agents

Screening assays can be based upon any of a variety of techniquesreadily available and known to one of ordinary skill in the art. Ingeneral, the screening assays involve contacting a cancerous cell with acandidate agent, and assessing the effect upon biological activity of adifferentially expressed gene product. The effect upon a biologicalactivity can be detected by, for example, detection of expression of agene product of a differentially expressed gene (e.g., a decrease inmRNA or polypeptide levels, would in turn cause a decrease in biologicalactivity of the gene product). Alternatively or in addition, the effectof the candidate agent can be assessed by examining the effect of thecandidate agent in a functional assay. For example, where thedifferentially expressed gene product is an enzyme, then the effect uponbiological activity can be assessed by detecting a level of enzymaticactivity associated with the differentially expressed gene product. Thefunctional assay will be selected according to the differentiallyexpressed gene product. In general, where the differentially expressedgene is increased in expression in a cancerous cell, agents of interestare those that decrease activity of the differentially expressed geneproduct.

Assays described infra can be readily adapted in the screening assayembodiments of the invention. Exemplary assays useful in screeningcandidate agents include, but are not limited to, hybridization-basedassays (e.g., use of nucleic acid probes or primers to assess expressionlevels), antibody-based assays (e.g., to assess levels of polypeptidegene products), binding assays, (e.g., to detect interaction of acandidate agent with a differentially expressed polypeptide, whichassays may be competitive assays where a natural or synthetic ligand forthe polypeptide is available), and the like; Additional exemplary assaysinclude, but are not necessarily limited to, cell proliferation assays,antisense knockout assays, assays to detect inhibition of cell cycle,assays of induction of cell death/apoptosis, and the like. Generallysuch assays are conducted in vitro, but many assays can be adapted forin vivo analyses, e.g., in an animal model of the cancer.

Identification of Therapeutic Targets

In another embodiment, the invention contemplates identification ofdifferentially expressed genes and gene products as therapeutic targets.In some respects, this is the converse of the assays described above foridentification of agents having activity in modulating (e.g., decreasingor increasing) activity of a differentially expressed gene product.

In this embodiment, therapeutic targets are identified by examining theeffect(s) of an agent that can be demonstrated or has been-demonstratedto modulate a cancerous phenotype (e.g., inhibit or suppress or preventdevelopment of a cancerous phenotype). Such agents are generallyreferred to herein as an “anti-cancer agent”, which agents encompasschemotherapeutic agents. For example, the agent can be an antisenseoligonucleotide that is specific for a selected gene transcript. Forexample, the antisense oligonucleotide may have a sequence correspondingto a sequence of a differentially expressed gene described herein, e.g.,a sequence of one of SEQ ID NOS:1-23767.

Assays for identification of therapeutic targets can be conducted in avariety of ways using methods that are well known to one of ordinaryskill in the art. For example, a test cancerous cell that expresses oroverexpresses a differentially expressed gene is contacted with ananti-cancer agent, the effect upon a cancerous phenotype and abiological activity of the candidate gene product assessed. Thebiological activity of the candidate gene product can be assayed beexamining, for example, modulation of expression of a gene encoding thecandidate gene product (e.g., as detected by, for example, an increaseor decrease in transcript levels or polypeptide levels), or modulationof an enzymatic or other activity of the gene product. The cancerousphenotype can be, for example, cellular proliferation, loss of contactinhibition of growth (e.g., colony formation), tumor growth (in vitro orin vivo), and the like. Alternatively or in addition, the effect ofmodulation of a biological activity of the candidate target gene uponcell death/apoptosis or cell cycle regulation can be assessed.

Inhibition or suppression of a cancerous phenotype, or an increase incell death or apoptosis as a result of modulation of biological activityof a candidate gene product indicates that the candidate gene product isa suitable target for cancer therapy. Assays described infra can bereadily adapted for assays for identification of therapeutic targets.Generally such assays are conducted in vitro, but many assays can beadapted for in vivo analyses, e.g., in an appropriate, art-acceptedanimal model of the cancer.

Candidate Agents

The term “agent” as used herein describes any molecule, e.g. protein orpharmaceutical, with the capability of modulating a biological activityof a gene product of a differentially expressed gene. Generally aplurality of assay mixtures are run in parallel with different agentconcentrations to obtain a differential response to the variousconcentrations. Typically, one of these concentrations serves as anegative control, i.e. at zero concentration or below the level ofdetection.

Candidate agents encompass numerous chemical classes, though typicallythey are organic molecules, preferably small organic compounds having amolecular weight of more than 50 and less than about 2,500 daltons.Candidate agents comprise functional groups necessary for structuralinteraction with proteins, particularly hydrogen bonding, and typicallyinclude at least an amine, carbonyl, hydroxyl or carboxyl group,preferably at least two of the functional chemical groups. The candidateagents often comprise cyclical carbon or heterocyclic structures and/oraromatic or polyaromatic structures substituted with one or more of theabove functional groups. Candidate agents are also found amongbiomolecules including, but not limited to: peptides, saccharides, fattyacids, steroids, purines, pyrimidines, derivatives, structural analogsor combinations thereof.

Candidate agents are obtained from a wide variety of sources includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including expression of randomizedoligonucleotides and oligopeptides. Alternatively, libraries of naturalcompounds in the form of bacterial, fungal, plant and animal extracts(including extracts from human tissue to identify endogenous factorsaffecting differentially expressed gene products) are available orreadily produced. Additionally, natural or synthetically producedlibraries and compounds are readily modified through conventionalchemical, physical and biochemical means, and may be used to producecombinatorial libraries. Known pharmacological agents may be subjectedto directed or random chemical modifications, such as acylation,alkylation, esterification, amidification, etc. to produce structuralanalogs.

Exemplary candidate agents of particular interest include, but are notlimited to, antisense and RNAi polynucleotides, and antibodies, solublereceptors, and the like. Antibodies and soluble receptors are ofparticular interest as candidate agents where the target differentiallyexpressed gene product is secreted or accessible at the cell-surface(e.g., receptors and other molecule stably-associated with the outercell membrane).

For method that involve RNAi (RNA interference), a double stranded RNA(dsRNA) molecule is usually used. The dsRNA is prepared to besubstantially identical to at least a segment of a subjectpolynucleotide (e.g. a cDNA or gene). In general, the dsRNA is selectedto have at least 70%, 75%, 80%, 85% or 90% sequence identity with thesubject polynucleotide over at least a segment of the candidate gene. Inother instances, the sequence identity is even higher, such as 95%, 97%or 99%, and in still other instances, there is 100% sequence identitywith the subject polynucleotide over at least a segment of the subjectpolynucleotide. The size of the segment over which there is sequenceidentity can vary depending upon the size of the subject polynucleotide.In general, however, there is substantial sequence identity over atleast 15, 20, 25, 30, 35, 40 or 50 nucleotides. In other instances,there is substantial sequence identity over at least 100, 200, 300, 400,500 or 1000 nucleotides; in still other instances, there is substantialsequence identity over the entire length of the subject polynucleotide,i.e., the coding and non-coding region of the candidate gene.

Because only substantial sequence similarity between the subjectpolynucleotide and the dsRNA is necessary, sequence variations betweenthese two species arising from genetic mutations, evolutionarydivergence and polymorphisms can be tolerated. Moreover, as describedfurther infra, the dsRNA can include various modified or nucleotideanalogs.

Usually the dsRNA consists of two separate complementary RNA strands.However, in some instances, the dsRNA may be formed by a single strandof RNA that is self-complementary, such that the strand loops back uponitself to form a hairpin loop. Regardless of form, RNA duplex formationcan occur inside or outside of a cell.

The size of the dsRNA that is utilized varies according to the size ofthe subject polynucleotide whose expression is to be suppressed and issufficiently long to be effective in reducing expression of the subjectpolynucleotide in a cell. Generally, the dsRNA is at least 10-15nucleotides long. In certain applications, the dsRNA is less than 20,21, 22, 23, 24 or 25 nucleotides in length. In other instances, thedsRNA is at least 50, 100, 150 or 200 nucleotides in length. The dsRNAcan be longer still in certain other applications, such as at least 300,400, 500 or 600 nucleotides. Typically, the dsRNA is not longer than3000 nucleotides. The optimal size for any particular subjectpolynucleotide can be determined by one of ordinary skill in the artwithout undue experimentation by varying the size of the dsRNA in asystematic fashion and determining whether the size selected iseffective in interfering with expression of the subject polynucleotide.

dsRNA can be prepared according to any of a number of methods that areknown in the art, including in vitro and in vivo methods, as well as bysynthetic chemistry approaches.

In vitro methods. Certain methods generally involve inserting thesegment corresponding to the candidate gene that is to be transcribedbetween a promoter or pair of promoters that are oriented to drivetranscription of the inserted segment and then utilizing an appropriateRNA polymerase to carry out transcription. One such arrangement involvespositioning a DNA fragment corresponding to the candidate gene orsegment thereof into a vector such that it is flanked by two opposablepolymerase-specific promoters that can be same or different.Transcription from such promoters produces two complementary RNA strandsthat can subsequently anneal to form the desired dsRNA. Exemplaryplasmids for use in such systems include the plasmid (PCR 4.0 TOPO)(available from Invitrogen). Another example is the vector pGEM-T(Promega, Madison, Wis.) in which the oppositely oriented promoters areT7 and SP6; the T3 promoter can also be utilized.

In a second arrangement, DNA fragments corresponding to the segment ofthe subject polynucleotide that is to be transcribed is inserted both inthe sense and antisense orientation downstream of a single promoter. Inthis system, the sense and antisense fragments are cotranscribed togenerate a single RNA strand that is self-complementary and thus canform dsRNA.

Various other in vitro methods have been described. Examples of suchmethods include, but are not-limited to, the methods described by Sadheret al. (Biochem. Int. 1-4:1015, 1987); by Bhattacharyya (Nature 343:484,1990); and by Livache, et al. (U.S. Pat. No. 5,795,715), each of whichis incorporated herein by reference in its entirety.

Single-stranded RNA can also be produced using a combination ofenzymatic and organic synthesis or by total organic synthesis. The useof synthetic chemical methods enable one to introduce desired modifiednucleotides or nucleotide analogs into the dsRNA.

In vivo methods. dsRNA can also be prepared in vivo according to anumber of established methods (see, e.g., Sambrook, et al. (1989)Molecular Cloning: A Laboratory Manual, 2^(nd) ed.; Transcription andTranslation (B. D. Hames, and S. J. Higgins, Eds., 1984); DNA Cloning,volumes I and II (D. N. Glover, Ed., 1985); and OligonucleotideSynthesis (M. J. Gait, Ed., 1984, each of which is incorporated hereinby reference in its entirety).

Once the single-stranded RNA has been formed, the complementary strandsare allowed to anneal to form duplex RNA. Transcripts are typicallytreated with DNAase and further purified according to establishedprotocols to remove proteins. Usually such purification methods are notconducted with phenol:chloroform. The resulting purified transcripts aresubsequently dissolved in RNAase free water or a buffer of suitablecomposition.

dsRNA is generated by annealing the sense and anti-sense RNA in vitro.Generally, the strands are initially denatured to keep the strandsseparate and to avoid self-annealing. During the annealing process,typically certain ratios of the sense and antisense strands are combinedto facilitate the annealing process. In some instances, a molar ratio ofsense to antisense strands of 3:7 is used; in other instances, a ratioof 4:6 is utilized; and in still other instances, the ratio is 1:1.

The buffer composition utilized during the annealing process can in someinstances affect the efficacy of the annealing process and subsequenttransfection procedure. While some have indicated that the bufferedsolution used to carry out the annealing process should include apotassium salt such as potassium chloride (e.g. at a concentration ofabout 80 mM). In some embodiments, the buffer is substantiallypostassium free. Once single-stranded RNA has annealed to form duplexRNA, typically any single-strand overhangs are removed using an enzymethat specifically cleaves such overhangs (e.g., RNAase A or RNAase T).

Once the dsRNA has been formed, it is introduced into a reference cell,which can include an individual cell or a population of cells (e.g., atissue, an embryo and an entire organism). The cell can be fromessentially any source, including animal, plant, viral, bacterial,fungal and other sources. If a tissue, the tissue can include dividingor nondividing and differentiated or undifferentiated cells. Further,the tissue can include germ line cells and somatic cells. Examples ofdifferentiated cells that can be utilized include, but are not limitedto, neurons, glial cells, blood cells, megakaryocytes, lymphocytes,macrophages, neutrophils, eosinophils, basophils, mast cells,leukocytes, granulocytes, keratinocytes, adipocytes, osteoblasts,osteoclasts, hepatocytes, cells of the endocrine or exocrine glands,fibroblasts, myocytes, cardiomyocytes, and endothelial cells. The cellcan be an individual cell of an embryo, and can be a blastocyte or anoocyte.

Certain methods are conducted using model systems for particularcellular states (e.g., a disease). For instance, certain methodsprovided herein are conducted with a cancer cell lines that serves as amodel system for investigating genes that are correlated with variouscancers.

A number of options can be utilized to deliver the dsRNA into a cell orpopulation of cells such as in a cell culture, tissue or embryo. Forinstance, RNA can be directly introduced intracellularly. Variousphysical methods are generally utilized in such instances, such asadministration by microinjection (see, e.g., Zernicka-Goetz, et al.(1997) Development 124:1133-1137; and Wianny, et al. (1998) Chromosoma107: 430-439).

Other options for cellular delivery include permeabilizing the cellmembrane and electroporation in the presence of the dsRNA,liposome-mediated transfection, or transfection using chemicals such ascalcium phosphate. A number of established gene therapy techniques canalso be utilized to introduce the dsRNA into a cell. By introducing aviral construct within a viral particle, for instance, one can achieveefficient introduction of an expression construct into the cell andtranscription of the RNA encoded by the construct.

If the dsRNA is to be introduced into an organism or tissue, gene guntechnology is an option that can be employed. This generally involvesimmobilizing the dsRNA on a gold particle which is subsequently firedinto the desired tissue. Research has also shown that mammalian cellshave transport mechanisms for taking in dsRNA (see, e.g., Asher, et al.(1969) Nature 223:715-717). Consequently, another delivery option is toadminister the dsRNA extracellularly into a body cavity, interstitialspace or into the blood system of the mammal for subsequent uptake bysuch transport processes. The blood and lymph systems and thecerebrospinal fluid are potential sites for injecting dsRNA. Oral,topical, parenteral, rectal and intraperitoneal administration are alsopossible modes of administration.

The composition introduced can also include various other agents inaddition to the dsRNA. Examples of such agents include, but are notlimited to, those that stabilize the dsRNA, enhance cellular uptakeand/or increase the extent of interference. Typically, the dsRNA isintroduced in a buffer that is compatible with the composition of thecell into which the RNA is introduced to prevent the cell from beingshocked. The minimum size of the dsRNA that effectively achieves genesilencing can also influence the choice of delivery system and solutioncomposition.

Sufficient dsRNA is introduced into the tissue to cause a detectablechange in expression of a taget gene (assuming the candidate gene is infact being expressed in the cell into which the dsRNA is introduced)using available detection methodologies. Thus, in some instances,sufficient dsRNA is introduced to achieve at least a 5-10% reduction incandidate gene expression as compared to a cell in which the dsRNA isnot introduced. In other instances, inhibition is at least 20, 30, 40,or 50%. In still other instances, the inhibition is at least 60, 70, 80,90 or 95%. Expression in some instances is essentially completelyinhibited to undetectable levels.

The amount of dsRNA introduced depends upon various factors such as themode of administration utilized, the size of the dsRNA, the number ofcells into which dsRNA is administered, and the age and size of ananimal if dsRNA is introduced into an animal. An appropriate amount canbe determined by those of ordinary skill in the art by initiallyadministering dsRNA at several different concentrations for example, forexample. In certain instances when dsRNA is introduced into a cellculture, the amount of dsRNA introduced into the cells varies from about0.5 to 3 μg per 10⁶ cells.

A number of options are available to detect interference of candidategene expression (i.e., to detect candidate gene silencing). In general,inhibition in expression is detected by detecting a decrease in thelevel of the protein encoded by the candidate gene, determining thelevel of mRNA transcribed from the gene and/or detecting a change inphenotype associated with candidate gene expression.

Use of Polypeptides to Screen for Peptide Analogs and Antagonists

Polypeptides encoded by differentially expressed genes identified hereincan be used to screen peptide libraries to identify binding partners,such as receptors, from among the encoded polypeptides. Peptidelibraries can be synthesized according to methods known in the art (see,e.g., U.S. Pat. No. 5,010,175 and WO 91/17823).

Agonists or antagonists of the polypeptides of the invention can bescreened using any available method known in the art, such as signaltransduction, antibody binding, receptor binding, mitogenic assays,chemotaxis assays, etc. The assay conditions ideally should resemble theconditions under which the native activity is exhibited in vivo, thatis, under physiologic pH, temperature, and ionic strength. Suitableagonists or antagonists will exhibit strong inhibition or enhancement ofthe native activity at concentrations that do not cause toxic sideeffects in the subject. Agonists or antagonists that compete for bindingto the native polypeptide can require concentrations equal to or greaterthan the native concentration, while inhibitors capable of bindingirreversibly to the polypeptide can be added in concentrations on theorder of the native concentration.

Such screening and experimentation can lead to identification of apolypeptide binding partner, such as a receptor, encoded by a gene or acDNA corresponding to a polynucleotide described herein, and at leastone peptide agonist or antagonist of the binding partner. Such agonistsand antagonists can be used to modulate, enhance, or inhibit receptorfunction in cells to which the receptor is native, or in cells thatpossess the receptor as a result of genetic engineering. Further, if thereceptor shares biologically important characteristics with a knownreceptor, information about agonist/antagonist binding can facilitatedevelopment of improved agonists/antagonists of the known receptor.

Vaccines and Uses

The differentially expressed nucleic acids and polypeptides produced bythe nucleic acids of the invention can also be used to modulate primaryimmune response to prevent or treat cancer. Every immune response is acomplex and intricately regulated sequence of events involving severalcell types. It is triggered when an antigen enters the body andencounters a specialized class of cells called antigen-presenting cells(APCs). These APCs capture a minute amount of the antigen and display itin a form that can be recognized by antigen-specific helper Tlymphocytes. The helper (Th) cells become activated and, in turn,promote the activation of other classes of lymphocytes, such as B cellsor cytotoxic T cells. The activated lymphocytes then proliferate andcarry out their specific effector functions, which in many casessuccessfully activate or eliminate the antigen. Thus, activating theimmune response to a particular antigen associated with a cancer cellcan protect the patient from developing cancer or result in lymphocyteseliminating cancer cells expressing the antigen.

Gene products, including polypeptides, mRNA (particularly mRNAs havingdistinct secondary and/or tertiary structures), cDNA, or complete gene,can be prepared and used in vaccines for the treatment or prevention ofhyperproliferative disorders and cancers. The nucleic acids andpolypeptides can be utilized to enhance the immune response, preventtumor progression, prevent hyperproliferative cell growth, and the like.Methods for selecting nucleic acids and polypeptides that are capable ofenhancing the immune response are known in the art. Preferably, the geneproducts for use in a vaccine are gene products which are present on thesurface of a cell and are recognizable by lymphocytes and antibodies.

The gene products may be formulated with pharmaceutically acceptablecarriers into pharmaceutical compositions by methods known in the art.The composition is useful as a vaccine to prevent or treat cancer. Thecomposition may further comprise at least one co-immunostimulatorymolecule, including but not limited to one or more majorhistocompatibility complex (MHC) molecules, such as a class I or classII molecule, preferably a class I molecule. The composition may furthercomprise other stimulator molecules including B7.1, B7.2, ICAM-1,ICAM-2, LFA-1, LFA-3, CD72 and the like, immunostimulatorypolynucleotides (which comprise an 5′-CG-3′ wherein the cytosine isunmethylated), and cytokines which include but are not limited to IL-1through IL-15, TNF-α, IFN-γ, RANTES, G-CSF, M-CSF, IFN-α, CTAP III,ENA-78, GRO, I-309, PF-4, IP-10, LD-78, MGSA, MIP-1α, MIP-1β, orcombination thereof, and the like for immunopotentiation. In oneembodiment, the immunopotentiators of particular interest are those thatfacilitate a Th1 immune response.

The gene products may also be prepared with a carrier that will protectthe gene products against rapid elimination from the body, such as acontrolled release formulation, including implants and microencapsulateddelivery systems. Biodegradable polymers can be used, such as ethylenevinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, polylactic acid, and the like. Methods for preparationof such formulations are known in the art.

In the methods of preventing or treating cancer, the gene products maybe administered via one of several routes including but not limited totransdermal, transmucosal, intravenous, intramuscular, subcutaneous,intradermal, intraperitoneal, intrathecal, intrapleural, intrauterine,rectal, vaginal, topical, intratumor, and the like. For transmucosal ortransdermal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art, and include, for example, administration bile saltsand fusidic acid derivatives. In addition, detergents may be used tofacilitate permeation. Transmucosal administration may be by nasalsprays or suppositories. For oral administration, the gene products areformulated into conventional oral administration form such as capsules,tablets, elixirs and the like.

The gene product is administered to a patient in an amount effective toprevent or treat cancer. In general, it is desirable to provide thepatient with a dosage of gene product of at least about 1 pg per Kg bodyweight, preferably at least about 1 ng per Kg body weight, morepreferably at least about 1 μg or greater per Kg body weight of therecipient. A range of from about 1 ng per Kg body weight to about 100 mgper Kg body weight is preferred although a lower or higher dose may beadministered. The dose is effective to prime, stimulate and/or cause theclonal expansion of antigen-specific T lymphocytes, preferably cytotoxicT lymphocytes, which in turn are capable of preventing or treatingcancer in the recipient. The dose is administered at least once and maybe provided as a bolus or a continuous administration. Multipleadministrations of the dose over a period of several weeks to months maybe preferable. Subsequent doses may be administered as indicated.

In another method of treatment, autologous cytotoxic lymphocytes ortumor infiltrating lymphocytes may be obtained from a patient withcancer. The lymphocytes are grown in culture, and antigen-specificlymphocytes are expanded by culturing in the presence of the specificgene products alone or in combination with at least oneco-immunostimulatory molecule with cytokines. The antigen-specificlymphocytes are then infused back into the patient in an amounteffective to reduce or eliminate the tumors in the patient. Cancervaccines and their uses are further described in U.S. Pat. No.5,961,978; U.S. Pat. No. 5,993,829; U.S. Pat. No. 6,132,980; and WO00/38706.

Pharmaceutical Compositions and Uses

Pharmaceutical compositions can comprise polypeptides, receptors thatspecifically bind a polypeptide produced by a differentially expressedgene (e.g., antibodies, or polynucleotides (including antisensenucleotides and ribozymes) of the claimed invention in a therapeuticallyeffective amount. The compositions can be used to treat primary tumorsas well as metastases of primary tumors. In addition, the pharmaceuticalcompositions can be used in conjunction with conventional methods ofcancer treatment, e.g., to sensitize tumors to radiation or conventionalchemotherapy.

Where the pharmaceutical composition comprises a receptor (such as anantibody) that specifically binds to a gene product encoded by adifferentially expressed gene, the receptor can be coupled to a drug fordelivery to a treatment site or coupled to a detectable label tofacilitate imaging of a site comprising cancer cells. Methods forcoupling antibodies to drugs and detectable labels are well known in theart, as are methods for imaging using detectable labels.

The term “therapeutically effective amount” as used herein refers to anamount of a therapeutic agent to treat, ameliorate, or prevent a desireddisease or condition, or to exhibit a detectable therapeutic orpreventative effect. The effect can be detected by, for example,chemical markers or antigen levels. Therapeutic effects also includereduction in physical symptoms, such as decreased body temperature.

The precise effective amount for a subject will depend upon thesubject's size and health, the nature and extent of the condition, andthe therapeutics or combination of therapeutics selected foradministration. Thus, it is not useful to specify an exact effectiveamount in advance. However, the effective amount for a given situationis determined by routine experimentation and is within the judgment ofthe clinician. For purposes of the present invention, an effective dosewill generally be from about 0.01 mg/kg to 50 mg/kg or 0.05 mg/kg toabout 10 mg/kg of the DNA constructs in the individual to which it isadministered.

A pharmaceutical composition can also contain a pharmaceuticallyacceptable carrier. The term “pharmaceutically acceptable carrier”refers to a carrier for administration of a therapeutic agent, such asantibodies or a polypeptide, genes, and other therapeutic agents. Theterm refers to any pharmaceutical carrier that does not itself inducethe production of antibodies harmful to the individual receiving thecomposition, and which can be administered without undue toxicity.Suitable carriers can be large, slowly metabolized macromolecules suchas proteins, polysaccharides, polylactic acids, polyglycolic acids,polymeric amino acids, amino acid copolymers, lipid aggregates andinactive virus particles. Such carriers are well known to those ofordinary skill in the art. Pharmaceutically acceptable carriers intherapeutic compositions can include liquids such as water, saline,glycerol and ethanol. Auxiliary substances, such as wetting oremulsifying agents, pH buffering substances, and the like, can also bepresent in such vehicles.

Typically, the therapeutic compositions are prepared as injectables,either as liquid solutions or suspensions; solid forms suitable forsolution in, or suspension in, liquid vehicles prior to injection canalso be prepared. Liposomes are included within the definition of apharmaceutically acceptable carrier. Pharmaceutically acceptable saltscan also be present in the pharmaceutical composition, e.g., mineralacid salts such as hydrochlorides, hydrobromides, phosphates, sulfates,and the like; and the salts of organic acids such as acetates,propionates, malonates, benzoates, and the like. A thorough discussionof pharmaceutically acceptable excipients is available in Remington: TheScience and Practice of Pharmacy (1995) Alfonso Gennaro, Lippincott,Williams, & Wilkins.

Delivery Methods

Once formulated, the compositions contemplated by the invention can be(1) administered directly to the subject (e.g., as polynucleotide,polypeptides, small molecule agonists or antagonists, and the like); or(2) delivered ex vivo, to cells derived from the subject (e.g., as in exvivo gene therapy). Direct delivery of the compositions will generallybe accomplished by parenteral injection, e.g., subcutaneously,intraperitoneally, intravenously or intramuscularly, intratumoral or tothe interstitial space of a tissue. Other modes of administrationinclude oral and pulmonary administration, suppositories, andtransdermal applications, needles, and gene guns or hyposprays. Dosagetreatment can be a single dose schedule or a multiple dose schedule.

Methods for the ex vivo delivery and reimplantation of transformed cellsinto a subject are known in the art and described in e.g., InternationalPublication No. WO 93/14778. Examples of cells useful in ex vivoapplications include, for example, stem cells, particularlyhematopoetic, lymph cells, macrophages, dendritic cells, or tumor cells.Generally, delivery of nucleic acids for both ex vivo and in vitroapplications can be accomplished by, for example, dextran-mediatedtransfection, calcium phosphate precipitation, polybrene mediatedtransfection, protoplast fusion, electroporation, encapsulation of thepolynucleotide(s) in liposomes, and direct microinjection of the DNAinto nuclei, all well known in the art.

Once differential expression of a gene corresponding to a polynucleotidedescribed herein has been found to correlate with a proliferativedisorder, such as neoplasia, dysplasia, and hyperplasia, the disordercan be amenable to treatment by administration of a therapeutic agentbased on the provided polynucleotide, corresponding polypeptide or othercorresponding molecule (e.g., antisense, ribozyme, etc.). In otherembodiments, the disorder can be amenable to treatment by administrationof a small molecule drug that, for example, serves as an inhibitor(antagonist) of the function of the encoded gene product of a genehaving increased expression in cancerous cells relative to normal cellsor as an agonist for gene products that are decreased in expression incancerous cells (e.g., to promote the activity of gene products that actas tumor suppressors).

The dose and the means of administration of the inventive pharmaceuticalcompositions are determined based on the specific qualities of thetherapeutic composition, the condition, age, and weight of the patient,the progression of the disease, and other relevant factors. For example,administration of polynucleotide therapeutic composition agents includeslocal or systemic administration, including injection, oraladministration, particle gun or catheterized administration, and topicaladministration. In general, the therapeutic polynucleotide compositioncontains an expression construct comprising a promoter operably linkedto a polynucleotide of at least 12, 22, 25, 30, or 35 contiguous nt ofthe polynucleotide disclosed herein. Various methods can be used toadminister the therapeutic composition directly to a specific site inthe body. For example, a small metastatic lesion is located and thetherapeutic composition injected several times in several differentlocations within the body of the tumor. Alternatively, arteries whichserve a tumor are identified, and the therapeutic composition injectedinto such an artery, in order to deliver the composition directly intothe tumor. A tumor that has a necrotic center is aspirated and thecomposition injected directly into the now empty center of the tumor.The antisense composition is directly administered to the surface of thetumor, for example, by topical application of the composition. X-rayimaging is used to assist in certain of the above delivery methods.

Targeted delivery of therapeutic compositions containing an antisensepolynucleotide, subgenomic polynucleotides, or antibodies to specifictissues can also be used. Receptor-mediated DNA delivery techniques aredescribed in, for example, Findeis et al., Trends Biotechnol. (1993)11:202; Chiou et al., Gene Therapeutics: Methods And Applications OfDirect Gene Transfer (J. A. Wolff, ed.) (1994); Wu et al., J. Biol.Chem. (1988) 263:621; Wu et al., J. Biol. Chem. (1994) 269:542; Zenke etal., Proc. Natl. Acad. Sci. (USA) (1990) 87:3655; Wu et al., J. Biol.Chem. (1991) 266:338. Therapeutic compositions containing apolynucleotide are administered in a range of about 100 ng to about 200mg of DNA for local administration in a gene therapy protocol.Concentration ranges of about 500 ng to about 50 mg, about 1 μg to about2 mg, about 5 μg to about 500 μg, and about 20 μg to about 100 :g of DNAcan also be used during a gene therapy protocol. Factors such as methodof action (e.g., for enhancing or inhibiting levels of the encoded geneproduct) and efficacy of transformation and expression areconsiderations that will affect the dosage required for ultimateefficacy of the antisense subgenomic polynucleotides.

The therapeutic polynucleotides and polypeptides of the presentinvention can be delivered using gene delivery vehicles. The genedelivery vehicle can be of viral or non-viral origin (see generally,Jolly, Cancer Gene Therapy (1994) 1:51; Kimura, Human Gene Therapy(1994) 5:845; Connelly, Human Gene Therapy (1995)1:185; and Kaplitt,Nature Genetics (1994) 6:148). Expression of such coding sequences canbe induced using endogenous mammalian or heterologous promoters.Expression of the coding sequence can be either constitutive orregulated.

Viral-based vectors for delivery of a desired polynucleotide andexpression in a desired cell are well known in the art. Exemplaryviral-based vehicles include, but are not limited to, recombinantretroviruses (see, e.g., WO 90/07936; WO 94/03622; WO 93/25698; WO93/25234; U.S. Pat. No. 5,219,740; WO 93/11230; WO 93/10218; U.S. Pat.No. 4,777,127; GB Patent No. 2,200,651; EP 0 345 242; and WO 91/02805),alphavirus-based vectors (e.g., Sindbis virus vectors, Semliki forestvirus (ATCC VR-67; ATCC VR-1247), Ross River virus (ATCC VR-373; ATCCVR-1246) and Venezuelan equine encephalitis virus (ATCC VR-923; ATCCVR-1250; ATCC VR 1249; ATCC VR-532), and adeno-associated virus (AAV)vectors (see, e.g., WO 94/12649, WO 93/03769; WO 93/19191; WO 94/28938;WO 95/11984 and WO 95/00655). Administration of DNA linked to killedadenovirus as described in Curiel, Hum. Gene Ther. (1992) 3:147 can alsobe employed.

Non-viral delivery vehicles and methods can also be employed, including,but not limited to, polycationic condensed DNA linked or unlinked tokilled adenovirus alone (see, e.g., Curiel, Hum. Gene Ther. (1992)3:147); ligand-linked DNA (see, e.g., Wu, J. Biol. Chem. (1989)264:16985); eukaryotic cell delivery vehicles cells (see, e.g., U.S.Pat. No. 5,814,482; WO 95/07994; WO 96/17072; WO 95/30763; and WO97/42338) and nucleic charge neutralization or fusion with cellmembranes. Naked DNA can also be employed. Exemplary naked DNAintroduction methods are described in WO 90/11092 and U.S. Pat. No.5,580,859. Liposomes that can act as gene delivery vehicles aredescribed in U.S. Pat. No. 5,422,120; WO 95/13796; WO 94/23697; WO91/14445; and EP 0524968. Additional approaches are described in Philip,Mol. Cell Biol. (1994) 14:2411, and in Woffendin, Proc. Natl. Acad. Sci.(1994) 91:1581.

The sequences disclosed in this patent application were disclosed inseveral earlier patent applications. The relationship between the SEQ IDNOS in those earlier application and the SEQ ID NOS disclosed herein isshown in Tables 161 and 162. TABLE 161 relationship between SEQ ID NOs.this patent application and SEQ ID NOs of parent patent applications SEQIDs corresponding parent parent in parent SEQ IDs in this caseapplication no. filing date case patent application 1480 10/076,555 Feb.15, 2002 1-844   1-844 1481 09/297,648 Mar. 10, 2000 1-5252  845-60961487 09/313,292 May 13, 1999 1-2707 6097-8803 1490 09/854,124 May 10,2001 1-37  8804-8840 1492 09/404,706 Sep. 23, 1999 1-1079 8841-9919 159810/629,771 Jul. 28, 2003 1-3351  9920-13270 1624 09/803,719 Mar. 9, 20011-2396 13271-15666 1625 10/609,021 Jun. 26, 2003 1-324  15667-1599015990 10/615,618 Jul. 7, 2003 1-6010 15991-22000 16252 10/012,697 Dec.7, 2001 1-1568 22001-23568 18790 60/532,830 Dec. 23, 2003 1-199 23569-23767

The disclosures of all prior U.S. applications to which the presentapplication claims priority, which includes those U.S. applicationsreferenced in the table above as well as their respective priorityapplications, are each incorporated herein by referenced in theirentireties for all purposes, including the disclosures found in theSequence Listings, tables, figures and Examples.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Example 1 Source of Biological Materials and Overview of NovelPolynucleotides Expressed by the Biological Materials

Human colon cancer cell line Km12L4-A (Morika, W. A. K. et al., CancerResearch (1988) 48:6863) was used to construct a cDNA library from mRNAisolated from the cells. As described in the above overview, a total of4,693 sequences expressed by the Km12L4-A cell line were isolated andanalyzed; most sequences were about 275-300 nucleotides in length. TheKM12L4-A cell line is derived from the KM12C cell line. The KM12C cellline, which is poorly metastatic (low metastatic) was established inculture from a Dukes' stage B₂ surgical specimen (Morikawa et al. CancerRes. (1988) 48:6863). The KML4-A is a highly metastatic subline derivedfrom KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling etal. Proc. Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12Cand KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) arewell-recognized in the art as a model cell line for the study of coloncancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. CancerRes. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin.Exp. Metastasis (1996) 14:246).

The sequences were first masked to eliminate low complexity sequencesusing the XBLAST masking program (Claverie “Effective Large-ScaleSequence Similarity Searches,” In: Computer Methods for MacromolecularSequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 AcademicPress, NY, N.Y. (1996); see particularly Claverie, in “Automated DNASequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993)17:191). Generally, masking does not influence the final search results,except to eliminate of relative little interest due to their loxcomplexity, and to eliminate multiple “hits” based on similarity torepetitive regions common to multiple sequences, e.g., Alu repeats.Masking resulted in the elimination of 43 sequences. The remainingsequences were then used in a BLASTN vs. Genbank search with searchparameters of greater than 70% overlap, 99% identity, and a p value ofless than 1×10⁻⁴⁰, which search resulted in the discarding of 1,432sequences. Sequences from this search also were discarded if theinclusive parameters were met, but the sequence was ribosomal orvector-derived.

The resulting sequences from the previous search were classified intothree groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP(non-redundant proteins) database search: (1) unknown (no hits in theGenbank search), (2) weak similarity (greater than 45% identity and pvalue of less than 1×10⁻⁵), and (3) high similarity (greater than 60%overlap, greater than 80% identity, and p value less than 1×10⁻⁵). Thissearch resulted in discard of 98 sequences as having greater than 70%overlap, greater than 99% identity, and p value of less than 1×10⁻⁴⁰.

The remaining sequences were classified as unknown (no hits), weaksimilarity, and high similarity (parameters as above). Two searches wereperformed on these sequences. First, a BLAST vs. EST database searchresulted in discard of 1771 sequences (sequences with greater than 99%overlap, greater than 99% similarity and a p value of less than 1×10⁻⁴⁰;sequences with a p value of less than 1×10⁻⁶⁵ when compared to adatabase sequence of human origin were also excluded). Second, a BLASTNvs. Patent GeneSeq database resulted in discard of 15 sequences (greaterthan 99% identity; p value less than 1×10⁻⁴⁰; greater than 99% overlap).

The remaining sequences were subjected to screening using other rulesand redundancies in the dataset. Sequences with a p value of less than1×10⁻¹¹¹ in relation to a database sequence of human origin werespecifically excluded. The final result provided the 404 sequenceslisted in the accompanying Sequence Listing. The Sequence Listing isarranged beginning with sequences with no similarity to any sequence ina database searched, and ending with sequences with the greatestsimilarity. Each identified polynucleotide represents sequence from atleast a partial mRNA transcript. Polynucleotides that were determined tobe novel were assigned a sequence identification number.

The novel polynucleotides and were assigned sequence identificationnumbers SEQ ID NOS: 1-404. The DNA sequences corresponding to the novelpolynucleotides are provided in the Sequence Listing. The majority ofthe sequences are presented in the Sequence Listing in the 5′ to 3′direction. A small number, 25, are listed in the Sequence Listing in the5′ to 3′ direction but the sequence as written is actually 3′ to 5′.These sequences are readily identified with the designation “AR” in theSequence Name in Table 1 (inserted before the claims). The sequencescorrectly listed in the 5′ to 3′ direction in the Sequence Listing aredesignated “AF.” The Sequence Listing filed herewith therefore contains25 sequences listed in the reverse order, namely SEQ ID NOS:47, 97, 137,171, 173, 179, 182, 194, 200, 202, 213, 227, 258, 264, 275, 302, 313,324, 329, 330, 331, 338, 358, 379, and 404.

Because the provided polynucleotides represent partial mRNA transcripts,two or more polynucleotides of the invention may represent differentregions of the same mRNA transcript and the same gene. Thus, if two ormore SEQ ID NOS: are identified as belonging to the same clone, theneither sequence can be used to obtain the full-length mRNA or gene.

In order to confirm the sequences of SEQ ID NOS:1-404, inserts of theclones corresponding to these polynucleotides were re-sequenced. These“validation” sequences are provided in SEQ ID NOS:405-800. Thesevalidation sequences were often longer than the original polynucleotidesequences. They validate, and thus often provide additional sequenceinformation. Validation sequences can be correlated with the originalsequences they validate by identifying those sequences of SEQ IDNOS:1-404 and the validation sequences of SEQ ID NOS:405-800 that sharethe same clone name in Table 1. TABLE 1 Sequence identification numbers,cluster ID, sequence name, and clone name SEQ ID NO: Cluster ID SequenceName Clone Name 1 4635 RTA00000180AF.i.20.1 M00001429B:A11 2RTA00000185AF.n.12.1 M00001608D:A11 3 4622 RTA00000187AF.m.15.2M00001686A:E06 4 3706 RTA00000191AF.i.17.2 M00004068B:A01 5 36535RTA00000181AF.f.5.1 M00001449A:G10 6 3990 RTA00000183AF.j.11.1M00001532B:A06 7 5319 RTA00000192AF.i.12.1 M00004169C:C12 8 36393RTA00000180AF.c.2.1 M00001417A:E02 9 2623 RTA00000183AF.a.6.1M00001497A:G02 10 7587 RTA00000178AF.n.24.1 M00001387B:G03 11 7065RTA00000137A.g.6.1 M00001557A:D02 12 10539 RTA00000187AF.l.7.1M00001680D:F08 13 27250 RTA00000181AF.g.10.1 M00001450A:D08 14 5556RTA00000179AF.n.10.1 M00001407B:D11 15 RTA00000192AF.m.12.1M00004191D:B11 16 8761 RTA00000184AF.k.12.1 M00001557D:D09 17 4622RTA00000189AF.g.1.1 M00003856B:C02 18 11460 RTA00000187AF.g.12.1M00001676B:F05 19 16283 RTA00000120A.o.20.1 M00001467A:D08 20 3430RTA00000191AF.a.9.1 M00003981A:E10 21 7065 RTA00000184AF.j.21.1M00001557A:D02 22 RTA00000182AF.l.20.1 M00001488B:F12 23RTA00000123A.g.19.1 M00001531A:H11 24 16918 RTA00000193AF.a.16.1M00004223A:G10 25 16914 RTA00000193AF.f.5.1 M00004275C:C11 26 40108RTA00000187AF.o.24.1 M00003741D:C09 27 14286 RTA00000193AF.f.22.1M00004283B:A04 28 17004 RTA00000186AF.b.21.1 M00001617C:E02 29RTA00000180AF.g.22.1 M00001426B:D12 30 13272 RTA00000192AF.e.3.1M00004138B:H02 31 RTA00000194AF.f.4.1 M00005180C:G03 32 32663RTA00000118A.l.8.1 M00001450A:A11 33 RTA00000180AF.a.9.1 M00001414A:B0134 5832 RTA00000178AF.o.23.1 M00001388D:G05 35 7801 RTA00000181AF.c.21.1M00001446A:F05 36 76760 RTA00000187AF.a.15.1 M00001657D:F08 37 40132RTA00000178AF.c.7.1 M00001365C:C10 38 RTA00000183AF.e.1.1 M00001505C:C0539 4016 RTA00000118A.c.4.1 M00001395A:C03 40 5382 RTA00000187AF.m.23.2M00001688C:F09 41 5693 RTA00000190AF.p.17.2 M00003978B:G05 42 307RTA00000136A.o.4.2 M00001552A:B12 43 39833 RTA00000178AF.i.23.1M00001378B:B02 44 RTA00000193AF.m.5.1 M00004359B:G02 45 5325RTA00000191AF.o.6.1 M00004093D:B12 46 5325 RTA00000191AF.o.6.2M00004093D:B12 47 18957 RTA00000190AR.m.9.1 M00003958A:H02 48 39508RTA00000120A.o.2.1 M00001467A:D04 49 22390 RTA00000136A.j.13.1M00001551A:G06 50 12170 RTA00000125A.h.18.4 M00001544A:E03 51 4393RTA00000187AF.n.17.1 M00001693C:G01 52 19 RTA00000182AF.b.7.1M00001463C:B11 53 RTA00000193AF.c.21.1 M00004249D:F10 54 7899RTA00000189AF.c.10.1 M00003837D:A01 55 40073 RTA00000191AF.e.3.1M00004028D:C05 56 7005 RTA00000179AF.o.22.1 M00001410A:D07 57RTA00000187AF.h.22.1 M00001679A:F06 58 18957 RTA00000190AF.m.9.2M00003958A:H02 59 18957 RTA00000183AF.h.23.1 M00001528A:F09 60 16283RTA00000182AF.c.22.1 M00001467A:D08 61 6974 RTA00000183AF.d.9.1M00001504C:H06 62 2623 RTA00000183AF.b.14.1 M00001500A:E11 63 9105RTA00000191AF.a.21.2 M00003983A:A05 64 13238 RTA00000181AF.m.4.1M00001455A:E09 65 5749 RTA00000185AF.a.19.1 M00001571C:H06 66 6455RTA00000193AF.b.9.1 M00004229B:F08 67 23001 RTA00000185AF.c.24.1M00001578B:E04 68 6455 RTA00000192AF.g.23.1 M00004157C:A09 69 13595RTA00000189AF.f.8.1 M00003851B:D10 70 39442 RTA00000120A.o.21.1M00001467A:E10 71 17036 RTA00000191AF.f.13.1 M00004035D:B06 72RTA00000183AF.g.9.1 M00001513B:G03 73 7005 RTA00000181AF.k.24.1M00001454B:C12 74 6268 RTA00000126A.o.23.1 M00001551A:B10 75 16130RTA00000119A.c.13.1 M00001453A:E11 76 23201 RTA00000187AF.a.14.1M00001657D:C03 77 5321 RTA00000183AF.k.8.1 M00001534A:F09 78 13157RTA00000186AF.a.6.1 M00001614C:F10 79 2102 RTA00000193AF.n.7.1M00004377C:F05 80 1058 RTA00000126A.e.20.3 M00001548A:H09 81 40392RTA00000180AF.j.8.1 M00001429D:D07 82 RTA00000183AF.e.23.1M00001506D:A09 83 11476 RTA00000187AF.p.19.1 M00003747D:C05 84 3584RTA00000177AF.h.20.1 M00001349B:B08 85 10470 RTA00000180AF.f.18.1M00001424B:G09 86 39425 RTA00000133A.f.1.1 M00001470A:C04 87 5175RTA00000184AF.f.3.1 M00001550A:G01 88 13576 RTA00000189AF.o.13.1M00003885C:A02 89 7665 RTA00000134A.l.19.1 M00001535A:B01 90 16927RTA00000177AF.h.9.3 M00001348B:B04 91 6660 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363 13913RTA00000186AF.e.6.1 M00001623D:F10 364 RTA00000192AF.c.2.1M00004121B:G01 365 3956 RTA00000183AF.g.3.1 M00001512D:G09 366 14364RTA00000183AF.g.12.1 M00001513C:E08 367 6880 RTA00000191AF.m.20.1M00004087D:A01 368 84182 RTA00000180AF.h.19.1 M00001428A:H10 369 2790RTA00000177AF.e.2.1 M00001343C:F10 370 4561 RTA00000184AF.i.21.1M00001555D:G10 371 8847 RTA00000180AF.b.16.1 M00001416B:H11 372 56020RTA00000193AF.g.2.1 M00004285B:E08 373 1531 RTA00000119A.o.3.1M00001461A:D06 374 6420 RTA00000177AF.f.10.3 M00001345A:E01 375RTA00000188AF.b.12.1 M00003754C:E09 376 RTA00000180AF.k.24.1M00001432C:F06 377 RTA00000184AF.a.8.1 M00001544A:E06 378 2696RTA00000134A.m.13.1 M00001536A:B07 379 260 RTA00000185AR.i.12.2M00001594B:H04 380 11350 RTA00000189AF.a.24.2 M00003826B:A06 381 2428RTA00000123A.l.21.1 M00001533A:C11 382 4313 RTA00000122A.n.3.1M00001517A:B07 383 RTA00000184AF.p.3.1 M00001566B:D11 384 697RTA00000188AF.d.6.1 M00003759B:B09 385 5619 RTA00000188AF.1.9.1M00003796C:D05 386 4568 RTA00000122A.d.15.3 M00001513A:B06 387RTA00000177AF.i.6.2 M00001350A:B08 388 5622 RTA00000178AF.a.11.1M00001362B:D10 389 7514 RTA00000184AF.k.21.1 M00001558B:H11 390 5619RTA00000189AF.f.17.1 M00003853A:D04 391 7570 RTA00000187AF.g.24.1M00001677D:A07 392 23358 RTA00000190AF.o.21.1 M00003974D:H02 393 23210RTA00000190AF.o.20.1 M00003974D:E07 394 5192 RTA00000184AF.k.2.1M00001557B:H10 395 13538 RTA00000180AF.a.24.1 M00001415A:H06 396RTA00000189AF.h.17.1 M00003867A:D10 397 RTA00000192AF.o.11.1M00004205D:F06 398 RTA00000184AF.1.11.1 M00001559B:F01 399 4718RTA00000189AF.g.5.1 M00003857A:H03 400 14929 RTA00000177AF.m.1.2M00001353D:D10 401 4908 RTA00000192AF.j.2.1 M00004171D:B03 402RTA00000178AF.k.16.1 M00001381D:E06 403 RTA00000194AF.c.24.1M00004692A:H08 404 17732 RTA00000178AR.i.2.2 M00001376B:G06 405 1706280.A1.sp6:130208.Seq M00001340B:A06 406 11589 80.B1.sp6:130220.SeqM00001340D:F10 407 4443 80.C1.sp6:130232.Seq M00001341A:E12 408 3980580.D1.sp6:130244.Seq M00001342B:E06 409 2790 80.E1.sp6:130256.SeqM00001343C:F10 410 23255 80.F1.sp6:130268.Seq M00001343D:H07 411 642080.G1.sp6:130280.Seq M00001345A:E01 412 5007 80.H1.sp6:130292.SeqM00001346A:F09 413 13576 80.D2.sp6:130245.Seq M00001347A:B10 414 1692780.E2.sp6:130257.Seq M00001348B:B04 415 16985 80.F2.sp6:130269.SeqM00001348B:G06 416 3584 80.G2.sp6:130281.Seq M00001349B:B08 41780.H2.sp6:130293.Seq M00001350A:B08 418 7187 80.A3.sp6:130210.SeqM00001350A:H01 419 16245 80.D3.sp6:130246.Seq M00001352A:E02 420 807880.E3.sp6:130258.Seq M00001353A:G12 421 14929 80.F3.sp6:130270.SeqM00001353D:D10 422 14391 80.G3.sp6:130282.Seq M00001355B:G10 423 414180.B4.sp6:130223.Seq M00001361A:A05 424 2379 80.C4.sp6:130235.SeqM00001361D:F08 425 5622 80.D4.sp6:130247.Seq M00001362B:D10 426 94580.E4.sp6:130259.Seq M00001362C:H11 427 40132 80.F4.sp6:130271.SeqM00001365C:C10 428 80.G4.sp6:130283.Seq M00001368D:E03 429 686780.H4.sp6:130295.Seq M00001370A:C09 430 7172 80.A5.sp6:130212.SeqM00001371C:E09 431 17732 80.B5.sp6:130224.Seq M00001376B:G06 432 3983380.C5.sp6:130236.Seq M00001378B:B02 433 1334 80.D5.sp6:130248.SeqM00001379A:A05 434 39886 80.E5.sp6:130260.Seq M00001380D:B09 43580.F5.sp6:130272.Seq M00001381D:E06 436 22979 80.G5.sp6:130284.SeqM00001382C:A02 437 39648 80.H5.sp6:130296.Seq M00001383A:C03 43880.B6.sp6:130225.Seq M00001384B:A11 439 5178 80.C6.sp6:130237.SeqM00001386C:B12 440 2464 80.D6.sp6:130249.Seq M00001387A:C05 441 758780.E6.sp6:130261.Seq M00001387B:G03 442 5832 80.F6.sp6:130273.SeqM00001388D:G05 443 16269 80.G6.sp6:130285.Seq M00001389A:C08 444 658380.H6.sp6:130297.Seq M00001394A:F01 445 4009 80.A7.sp6:130214.SeqM00001396A:C03 446 80.B7.sp6:130226.Seq M00001400B:H06 447 3956380.C7.sp6:130238.Seq M00001402A:E08 448 5556 80.D7.sp6:130250.SeqM00001407B:D11 449 9577 80.E7.sp6:130262.Seq M00001409C:D12 450 700580.F7.sp6:130274.Seq M00001410A:D07 451 8551 80.G7.sp6:130286.SeqM00001412B:B10 452 80.H7.sp6:130298.Seq M00001414A:B01 45380.A8.sp6:130215.Seq M00001414C:A07 454 13538 80.B8.sp6:130227.SeqM00001415A:H06 455 8847 80.C8.sp6:130239.Seq M00001416B:H11 456 3639380.D8.sp6:130251.Seq M00001417A:E02 457 9952 80.E8.sp6:130263.SeqM00001418B:F03 458 9577 80.G8.sp6:130287.Seq M00001421C:F01 459 1506680.H8.sp6:130299.Seq M00001423B:E07 460 10470 80.A9.sp6:130216.SeqM00001424B:G09 461 22195 80.B9.sp6:130228.Seq M00001425B:H08 46280.C9.sp6:130240.Seq M00001426B:D12 463 4261 80.D9.sp6:130252.SeqM00001426D:C08 464 84182 80.E9.sp6:130264.Seq M00001428A:H10 465 4039280.H9.sp6:130300.Seq M00001429D:D07 466 16731 80.C10.sp6:130241.SeqM00001442C:D07 467 80.D10.sp6:130253.Seq M00001443B:F01 468 1353280.E10.sp6:130265.Seq M00001445A:F05 469 8 80.H10.sp6:130301.SeqM00001448D:C09 470 36313 80.A11.sp6:130218.Seq M00001448D:H01 471 585780.B11.sp6:130230.Seq M00001449A:A12 472 41633 80.C11.sp6:130242.SeqM00001449A:B12 473 36535 80.D11.sp6:130254.Seq M00001449A:G10 474 8611080.E11.sp6:130266.Seq M00001449C:D06 475 32663 80.F11.sp6:130278.SeqM00001450A:A11 476 27250 80.G11.sp6:130290.Seq M00001450A:D08 477 1697080.H11.sp6:130302.Seq M00001452C:B06 478 16130 80.A12.sp6:130219.SeqM00001453A:E11 479 16653 80.B12.sp6:130231.Seq M00001453C:F06 480 700580.C12.sp6:130243.Seq M00001454B:C12 481 13072 80.F12.sp6:130279.SeqM00001455B:E12 482 9283 80.G12.sp6:130291.Seq M00001455D:F09 483 23255100.C1.sp6:131446.Seq M00001343D:H07 484 13576 100.E1.sp6:131470.SeqM00001347A:B10 485 7187 100.C2.sp6:131447.Seq M00001350A:H01 486 14391100.E3.sp6:131472.Seq M00001355B:G10 487 945 100.E4.sp6:131473.SeqM00001362G:H11 488 7172 100.A5.sp6:131426.Seq M00001371C:E09 489 39648100.A6.sp6:131427.Seq M00001383A:C03 490 84182 100.G9.sp6:131502.SeqM00001428A:H10 491 8 100.B11.sp6:131444.Seq M00001448D:C09 492 36535100.D11.sp6:131468.Seq M00001449A:G10 493 82498 100.F11.sp6:131492.SeqM00001450A:B12 494 16970 100.C12.sp6:131457.Seq M00001452C:B06 495 16130100.D12.sp6:131469.Seq M00001453A:E11 496 7005 121.D1.sp6:131917.SeqM00001454B:C12 497 121.G6.sp6:131958.Seq M00001506D:A09 498 18957121.F7.sp6:131947.Seq M00001528A:F09 499 40044 122.E1.sp6:132121.SeqM00001621C:C08 500 5214 122.C2.sp6:132098.Seq M00001630B:H09 501 6660122.B5.sp6:132089.Seq M00001679A:A06 502 13183 123.D5.sp6:132305.SeqM00004114C:F11 503 6455 123.E7.sp6:132319.Seq M00004157C:A09 504 5319123.F7.sp6:132331.Seq M00004169C:C12 505 11443 123.A8.sp6:132272.SeqM00004185C:C03 506 123.C8.sp6:132296.Seq M00004191D:B11 507 8210123.E8.sp6:132320.Seq M00004197D:H01 508 9457 123.D11.sp6:132311.SeqM00004307C:A06 509 6420 172.E1.sp6:133925.Seq M00001345A:E01 510 16245172.D2.sp6:133914.Seq M00001352A:E02 511 8078 172.C3.sp6:133903.SeqM00001353A:G12 512 14929 172.D3.sp6:133915.Seq M00001353D:D10 513 14391172.H3.sp6:133963.Seq M00001355B:G10 514 6583 172.B8.sp6:133896.SeqM00001394A:F01 515 4009 172.D8.sp6:133920.Seq M00001396A:C03 516172.B9.sp6:133897.Seq M00001400B:H06 517 176.A3.sp6:134514.SeqM00001632D:H07 518 19267 176.G3.sp6:134586.Seq M00001645A:C12 519 78091176.G5.sp6:134588.Seq M00001679C:F01 520 17055 176.D6.sp6:134553.SeqM00001682C:B12 521 6539 176.D9.sp6:134556.Seq M00003844C:B11 522177.H4.sp6:134791.Seq M00004121B:G01 523 5257 177.F5.sp6:134768.SeqM00004146C:C11 524 11494 177.E6.sp6:134757.Seq M00004172C:D08 525177.G7.sp6:134782.Seq M00004205D:F06 526 11451 177.D8.sp6:134747.SeqM00004214C:H05 527 9283 173.D2.SP6:134106.Seq M00001455D:F09 528 16283173.F3.SP6:134131.Seq M00001467A:D08 529 10539 173.B5.SP6:134085.SeqM00001499B:A11 530 6420 173.F5.SP6:134133.Seq M00001504D:G06 531 3956173.H5.SP6:134157.Seq M00001512D:G09 532 173.G7.SP6:134147.SeqM00001544A:E06 533 1577 173.C9.SP6:134101.Seq M00001556A:F11 534 9635173.D9.SP6:134113.Seq M00001557A:F01 535 5192 173.E9.SP6:134125.SeqM00001557B:H10 536 6539 173.A12.SP6:134080.Seq M00001579D:C03 537 945180.C2.sp6:135940.Seq M00001362C:H11 538 7005 180.H5.sp6:136003.SeqM00001410A:D07 539 39304 180.G9.sp6:135995.Seq M00001450A:A02 540 27250180.B10.sp6:135936.Seq M00001450A:D08 541 35555 184.A5.sp6:135530.SeqM00001528A:C04 542 19255 184.B10.sp6:135547.Seq M00001545A:C03 543 6268184.C12.sp6:135561.Seq M00001551A:B10 544 3277 217.E1.sp6:139406.SeqM00001624A:B06 545 39171 217.A12.sp6:139369.Seq M00001644C:B07 546 11460219.F2.sp6:139035.Seq M00001676B:F05 547 10539 219.F6.sp6:139039.SeqM00001680D:F08 548 11476 219.H8.sp6:139065.Seq M00003747D:C05 549 401679.A1.sp6:130016.Seq M00001395A:C03 550 7674 79.C1.sp6:130040.SeqM00001416A:H01 551 3681 79.E1.sp6:130064.Seq M00001449A:D12 552 3930479.F1.sp6:130076.Seq M00001450A:A02 553 82498 79.G1.sp6:130088.SeqM00001450A:B12 554 84328 79.A2.sp6:130017.Seq M00001452A:B04 555 8685979.B2.sp6:130029.Seq M00001452A:B12 556 1120 79.C2.sp6:130041.SeqM00001452A:D08 557 85064 79.D2.sp6:130053.Seq M00001452A:F05 558 8310379.G2.sp6:130089.Seq M00001454A:A09 559 10145 79.F3.sp6:130078.SeqM00001465A:B11 560 16283 79.H3.sp6:130102.Seq M00001467A:D08 561 456879.D4.sp6:130055.Seq M00001513A:B06 562 4313 79.F4.sp6:130079.SeqM00001517A:B07 563 2428 79.A5.sp6:130020.Seq M00001533A:C11 564 3942379.C5.sp6:130044.Seq M00001535A:F10 565 39174 79.E5.sp6:130068.SeqM00001541A:H03 566 22113 79.F5.sp6:130080.Seq M00001542A:A09 567 1982979.H5.sp6:130104.Seq M00001544A:G02 568 13864 79.B6.sp6:130033.SeqM00001545A:D08 569 1058 79.F6.sp6:130081.Seq M00001548A:H09 570 401579.G6.sp6:130093.Seq M00001549A:B02 571 39180 79.A7.sp6:130022.SeqM00001551A:F05 572 307 79.C7.sp6:130046.Seq M00001552A:B12 573 3945879.D7.sp6:130058.Seq M00001552A:D11 574 39490 79.G7.sp6:130094.SeqM00001557A:F03 575 39486 79.B8.sp6:130035.Seq M00001561A:C05 576 3938079.E8.sp6:130071.Seq M00001587A:B11 577 1399 79.G8.sp6:130095.SeqM00001604A:B10 578 39391 79.A9.sp6:130024.Seq M00001604A:F05 579 626879.G9.sp6:130096.Seq M00001551A:B10 580 377.F4.sp6:141957.SeqM00004692A:H08 581 2448 89.A1.sp6:130667.Seq M00001460A:F06 582 153189.C1.sp6:130691.Seq M00001461A:D06 583 19 89.D1.sp6:130703.SeqM00001463C:B11 584 38759 89.F1.sp6:130727.Seq M00001467A:B07 585 3950889.G1.sp6:130739.Seq M00001467A:D04 586 16283 89.H1.sp6:130751.SeqM00001467A:D08 587 39442 89.A2.sp6:130668.Seq M00001467A:E10 588 758989.B2.sp6:130680.Seq M00001468A:F05 589 89.C2.sp6:130692.SeqM00001469A:A01 590 12081 89.D2.sp6:130704.Seq M00001469A:C10 591 1910589.E2.sp6:130716.Seq M00001469A:H12 592 1037 89.F2.sp6:130728.SeqM00001470A:B10 593 39425 89.G2.sp6:130740.Seq M00001470A:C04 594 3947889.H2.sp6:130752.Seq M00001471A:B01 595 89.B3.sp6:130681.SeqM00001487B:H06 596 89.C3.sp6:130693.Seq M00001488B:F12 597 1869989.D3.sp6:130705.Seq M00001490B:C04 598 7206 89.E3.sp6:130717.SeqM00001494D:F06 599 2623 89.F3.sp6:130729.Seq M00001497A:G02 600 1053989.G3.sp6:130741.Seq M00001499B:A11 601 5336 89.H3.sp6:130753.SeqM00001500A:C05 602 2623 89.A4.sp6:130670.Seq M00001500A:E11 603 944389.B4.sp6:130682.Seq M00001500C:E04 604 9685 89.C4.sp6:130694.SeqM00001501D:C02 605 89.D4.sp6:130706.Seq M00001504A:E01 606 1018589.E4.sp6:130718.Seq M00001504C:A07 607 6974 89.F4.sp6:130730.SeqM00001504C:H06 608 6420 89.G4.sp6:130742.Seq M00001504D:G06 60989.H4.sp6:130754.Seq M00001505C:C05 610 89.A5.sp6:130671.SeqM00001506D:A09 611 39168 89.B5.sp6:130683.Seq M00001507A:H05 612 3941289.C5.sp6:130695.Seq M00001511A:H06 613 39186 89.D5.sp6:130707.SeqM00001512A:A09 614 3956 89.E5.sp6:130719.Seq M00001512D:G09 61589.F5.sp6:130731.Seq M00001513B:G03 616 14364 89.G5.sp6:130743.SeqM00001513C:E08 617 40044 89.H5.sp6:130755.Seq M00001514C:D11 618 895289.A6.sp6:130672.Seq M00001518C:B11 619 35555 89.B6.sp6:130684.SeqM00001528A:C04 620 18957 89.C6.sp6:130696.Seq M00001528A:F09 621 835889.D6.sp6:130708.Seq M00001528B:H04 622 38085 89.E6.sp6:130720.SeqM00001531A:D01 623 89.F6.sp6:130732.Seq M00001531A:H11 624 399089.G6.sp6:130744.Seq M00001532B:A06 625 16921 89.H6.sp6:130756.SeqM00001534A:C04 626 5321 89.B7.sp6:130685.Seq M00001534A:F09 627 411989.C7.sp6:130697.Seq M00001534C:A01 628 20212 89.E7.sp6:130721.SeqM00001535A:C06 629 2696 89.F7.sp6:130733.Seq M00001536A:B07 630 3939289.G7.sp6:130745.Seq M00001536A:C08 631 39420 89.H7.sp6:130757.SeqM00001537A:F12 632 3389 89.A8.sp6:130674.Seq M00001537B:G07 633 828689.B8.sp6:130686.Seq M00001540A:D06 634 3765 89.C8.sp6:130698.SeqM00001541A:D02 635 39453 89.E8.sp6:130722.Seq M00001542A:E06 63689.F8.sp6:130734.Seq M00001542B:B01 637 89.H8.sp6:130758.SeqM00001544A:E06 638 6974 89.A9.sp6:130675.Seq M00001544B:B07 63989.B9.sp6:130687.Seq M00001545A:B02 640 19255 89.C9.sp6:130699.SeqM00001545A:C03 641 1267 89.D9.sp6:130711.Seq M00001546A:G11 642 589289.E9.sp6:130723.Seq M00001548A:E10 643 4193 89.G9.sp6:130747.SeqM00001549B:F06 644 16347 89.H9.sp6:130759.Seq M00001549C:E06 645 723989.A10.sp6:130676.Seq M00001550A:A03 646 5175 89.B10.sp6:130688.SeqM00001550A:G01 647 22390 89.C10.sp6:130700.Seq M00001551A:G06 648 326689.D10.sp6:130712.Seq M00001551C:G09 649 5708 89.E10.sp6:130724.SeqM00001552B:D04 650 89.F10.sp6:130736.Seq M00001552D:A01 651 829889.G10.sp6:130748.Seq M00001553A:H06 652 4573 89.H10.sp6:130760.SeqM00001553B:F12 653 22814 89.A11.sp6:130677.Seq M00001553D:D10 654 3953989.B11.sp6:130689.Seq M00001555A:B02 655 39195 89.C11.sp6:130701.SeqM00001555A:C01 656 4561 89.D11.sp6:130713.Seq M00001555D:G10 657 924489.E11.sp6:130725.Seq M00001556A:C09 658 1577 89.F11.sp6:130737.SeqM00001556A:F11 659 4386 89.H11.sp6:130761.Seq M00001556B:C08 660 1129489.A12.sp6:130678.Seq M00001556B:G02 661 5192 89.D12.sp6:130714.SeqM00001557B:H10 662 8761 89.E12.sp6:130726.Seq M00001557D:D09 66389.F12.sp6:130738.Seq M00001558A:H05 664 7514 89.G12.sp6:130750.SeqM00001558B:H11 665 89.H12.sp6:130762.Seq M00001559B:F01 666 655890.A1.sp6:130859.Seq M00001560D:F10 667 102 90.B1.sp6:130871.SeqM00001563B:F06 668 90.D1.sp6:130895.Seq M00001566B:D11 669 574990.E1.sp6:130907.Seq M00001571C:H06 670 6539 90.G1.sp6:130931.SeqM00001579D:C03 671 6293 90.A2.sp6:130860.Seq M00001583D:A10 67290.C2.sp6:130884.Seq M00001590B:F03 673 260 90.D2.sp6:130896.SeqM00001594B:H04 674 4837 90.E2.sp6:130908.Seq M00001597C:H02 675 1047090.F2.sp6:130920.Seq M00001597D:C05 676 16999 90.G2.sp6:130932.SeqM00001598A:G03 677 22794 90.H2.sp6:130944.Seq M00001601A:D08 678 1146590.A3.sp6:130861.Seq M00001607A:E11 679 7802 90.B3.sp6:130873.SeqM00001608A:B03 680 22155 90.C3.sp6:130885.Seq M00001608B:E03 68190.D3.sp6:130897.Seq M00001608D:A11 682 13157 90.E3.sp6:130909.SeqM00001614C:F10 683 17004 90.F3.sp6:130921.Seq M00001617C:E02 684 4031490.G3.sp6:130933.Seq M00001619C:F12 685 40044 90.H3.sp6:130945.SeqM00001621C:C08 686 13913 90.A4.sp6:130862.Seq M00001623D:F10 687 327790.B4.sp6:130874.Seq M00001624A:B06 688 4309 90.C4.sp6:130886.SeqM00001624C:F01 689 5214 90.D4.sp6:130898.Seq M00001630B:H09 69090.E4.sp6:130910.Seq M00001632D:H07 691 39171 90.F4.sp6:130922.SeqM00001644C:B07 692 19267 90.G4.sp6:130934.Seq M00001645A:C12 693 466590.H4.sp6:130946.Seq M00001648C:A01 694 90.A5.sp6:130863.SeqM00001651A:H01 695 23201 90.B5.sp6:130875.Seq M00001657D:C03 696 7676090.C5.sp6:130887.Seq M00001657D:F08 697 23218 90.D5.sp6:130899.SeqM00001662C:A09 698 35702 90.E5.sp6:130911.Seq M00001663A:E04 699 646890.F5.sp6:130923.Seq M00001669B:F02 700 14367 90.G5.sp6:130935.SeqM00001670C:H02 701 7015 90.H5.sp6:130947.Seq M00001673C:H02 702 877390.A6.sp6:130864.Seq M00001675A:C09 703 11460 90.B6.sp6:130876.SeqM00001676B:F05 704 7570 90.D6.sp6:130900.Seq M00001677D:A07 705 441690.E6.sp6:130912.Seq M00001678D:F12 706 6660 90.F6.sp6:130924.SeqM00001679A:A06 707 90.H6.sp6:130948.Seq M00001679A:F06 708 2687590.A7.sp6:130865.Seq M00001679A:F10 709 6298 90.B7.sp6:130877.SeqM00001679B:F01 710 78091 90.C7.sp6:130889.Seq M00001679C:F01 711 1075190.D7.sp6:130901.Seq M00001679D:D03 712 10539 90.F7.sp6:130925.SeqM00001680D:F08 713 17055 90.G7.sp6:130937.Seq M00001682C:B12 714 538290.A8.sp6:130866.Seq M00001688C:F09 715 4393 90.B8.sp6:130878.SeqM00001693C:G01 716 67252 90.C8.sp6:130890.Seq M00001716D:H05 717 4010890.D8.sp6:130902.Seq M00003741D:C09 718 11476 90.E8.sp6:130914.SeqM00003747D:C05 719 90.F8.sp6:130926.Seq M00003754C:E09 720 69790.G8.sp6:130938.Seq M00003759B:B09 721 90.H8.sp6:130950.SeqM00003761D:A09 722 17076 90.A9.sp6:130867.Seq M00003762C:B08 723 310890.B9.sp6:130879.Seq M00003763A:F06 724 67907 90.C9.sp6:130891.SeqM00003774C:A03 725 90.D9.sp6:130903.Seq M00003784D:D12 726 1135090.F9.sp6:130927.Seq M00003826B:A06 727 7899 90.H9.sp6:130951.SeqM00003837D:A01 728 7798 90.A10.sp6:130868.Seq M00003839A:D08 729 653990.B10.sp6:130880.Seq M00003844C:B11 730 6874 90.C10.sp6:130892.SeqM00003846B:D06 731 90.D10.sp6:130904.Seq M00003851B:D08 732 1359590.E10.sp6:130916.Seq M00003851B:D10 733 5619 90.F10.sp6:130928.SeqM00003853A:D04 734 10515 90.G10.sp6:130940.Seq M00003853A:F12 735 462290.H10.sp6:130952.Seq M00003856B:C02 736 3389 90.A11.sp6:130869.SeqM00003857A:G10 737 4718 90.B11.sp6:130881.Seq M00003857A:H03 73890.C11.sp6:130893.Seq M00003867A:D10 739 12977 90.F11.sp6:130929.SeqM00003875B:F04 740 8479 90.G11.sp6:130941.Seq M00003875C:G07 74190.H11.sp6:130953.Seq M00003875D:D11 742 7798 90.A12.sp6:130870.SeqM00003876D:E12 743 5345 90.B12.sp6:130882.Seq M00003879B:C11 744 3158790.C12.sp6:130894.Seq M00003879B:D10 745 14507 90.D12.sp6:130906.SeqM00003879D:A02 746 13576 90.F12.sp6:130930.Seq M00003885C:A02 74790.G12.sp6:130942.Seq M00003891C:H09 748 9285 90.H12.sp6:130954.SeqM00003906C:E10 749 39809 99.A1.sp6:131230.Seq M00003907D:A09 750 1631799.B1.sp6:131242.Seq M00003907D:H04 751 8672 99.C1.sp6:131254.SeqM00003909D:C03 752 12532 99.D1.sp6:131266.Seq M00003912B:D01 753 390099.E1.sp6:131278.Seq M00003914C:F05 754 23255 99.F1.sp6:131290.SeqM00003922A:E06 755 24488 99.C2.sp6:131255.Seq M00003968B:F06 756 4012299.D2.sp6:131267.Seq M00003970C:B09 757 23210 99.E2.sp6:131279.SeqM00003974D:E07 758 23358 99.F2.sp6:131291.Seq M00003974D:H02 759 343099.A3.sp6:131232.Seq M00003981A:E10 760 2433 99.B3.sp6:131244.SeqM00003982C:C02 761 9105 99.C3.sp6:131256.Seq M00003983A:A05 762 612499.D3.sp6:131268.Seq M00004028D:A06 763 40073 99.E3.sp6:131280.SeqM00004028D:C05 764 37285 99.H3.sp6:131316.Seq M00004035C:A07 765 1703699.A4.sp6:131233.Seq M00004035D:B06 766 3706 99.C4.sp6:131257.SeqM00004068B:A01 767 99.D4.sp6:131269.Seq M00004072A:C03 768 1506999.F4.sp6:131293.Seq M00004081C:D10 769 9285 99.H4.sp6:131317.SeqM00004086D:G06 770 6880 99.A5.sp6:131234.Seq M00004087D:A01 771 532599.C5.sp6:131258.Seq M00004093D:B12 772 7221 99.D5.sp6:131270.SeqM00004105C:A04 773 4937 99.E5.sp6:131282.Seq M00004108A:E06 774 687499.F5.sp6:131294.Seq M00004111D:A08 775 13183 99.G5.sp6:131306.SeqM00004114C:F11 776 99.H5.sp6:131318.Seq M00004121B:G01 777 1327299.A6.sp6:131235.Seq M00004138B:H02 778 5257 99.B6.sp6:131247.SeqM00004146C:C11 779 6455 99.D6.sp6:131271.Seq M00004157C:A09 780 531999.E6.sp6:131283.Seq M00004169C:C12 781 4908 99.F6.sp6:131295.SeqM00004171D:B03 782 11494 99.G6.sp6:131307.Seq M00004172C:D08 783 1144399.A7.sp6:131236.Seq M00004185C:C03 784 99.B7.sp6:131248.SeqM00004191D:B11 785 8210 99.C7.sp6:131260.Seq M00004197D:H01 786 1431199.D7.sp6:131272.Seq M00004203B:C12 787 99.E7.sp6:131284.SeqM00004205D:F06 788 12971 99.B8.sp6:131249.Seq M00004223D:E04 789 645599.C8.sp6:131261.Seq M00004229B:F08 790 7212 99.D8.sp6:131273.SeqM00004230B:C07 791 4905 99.H8.sp6:131321.Seq M00004269D:D06 792 1691499.A9.sp6:131238.Seq M00004275C:C11 793 16921 99.D9.sp6:131274.SeqM00004295D:F12 794 13046 99.E9.sp6:131286.Seq M00004296C:H07 795 945799.F9.sp6:131298.Seq M00004307C:A06 796 26295 99.G9.sp6:131310.SeqM00004312A:G03 797 21847 99.H9.sp6:131322.Seq M00004318C:D10 79899.H10.sp6:131323.Seq M00004505D:F08 799 99.B11.sp6:131252.SeqM00004692A:H08 800 99.D11.sp6:131276.Seq M00005180C:G03 801 39304RTA00000118A.j.21.1.Seq_THC151859 802 2428RTA00000123A.1.21.1.Seq_THC205063 803 1058RTA00000126A.e.20.3.Seq_THC217534 804 5097RTA00000134A.k.1.1.Seq_THC215869 805 20212RTA00000134A.1.22.1.Seq_THC128232 806 23255RTA00000177AF.e.14.3.Seq_THC228776 807 2790RTA00000177AF.e.2.1.Seq_THC229461 808 6420RTA00000177AF.f.10.3.Seq_THC226443 809 4059RTA00000177AF.n.18.3.Seq_THC123051 810RTA00000179AF.j.13.1.Seq_THC105720 811 9952RTA00000180AF.c.20.1.Seq_THC162284 812 13238RTA00000181AF.m.4.1.Seq_THC140691 813 9685RTA00000183AF.c.11.1.Seq_THC109544 814RTA00000183AF.c.24.1.Seq_THC125912 815 6420RTA00000183AF.d.11.1.Seq_THC226443 816 6974RTA00000183AF.d.9.1.Seq_THC223129 817 40044RTA00000183AF.g.22.1.Seq_THC232899 818 RTA00000183AF.g.9.1.Seq_THC198280819 5892 RTA00000184AF.d.11.1.Seq_THC161896 820 40044RTA00000186AF.d.1.1.Seq_THC232899 821 RTA00000186AF.h.14.1.Seq_THC112525822 19267 RTA00000186AF.1.12.1.Seq_THC178183 823 8773RTA00000187AF.f.24.1.Seq_THC220002 824 7570RTA00000187AF.g.24.1.Seq_THC168636 825 11476RTA00000187AF.p.19.1.Seq_THC108482 826RTA00000188AF.d.11.1.Seq_THC212094 827 17076RTA00000188AF.d.21.1.Seq_THC208760 828 697RTA00000188AF.d.6.1.Seq_THC178884 829 67907RTA00000188AF.g.11.1.Seq_THC123222 830 5619RTA00000188AF.1.9.1.Seq_THC167845 831 4718RTA00000189AF.g.5.1.Seq_THC196102 832 39809RTA00000190AF.e.3.1.Seq_THC150217 833 23255RTA00000190AF.j.4.1.Seq_THC228776 834 40122RTA00000190AF.n.23.1.Seq_THC109227 835 23210RTA00000190AF.o.20.1.Seq_THC207240 836 23358RTA00000190AF.o.21.1.Seq_THC207240 837 5693RTA00000190AF.p.17.2.Seq_THC173318 838 2433RTA00000191AF.a.15.2.Seq_THC79498 839 5257RTA00000192AF.f.3.1.Seq_THC213833 840 16392RTA00000192AF.l.1.1.Seq_THC202071 841 RTA00000193AF.c.21.1.Seq_THC222602842 26295 RTA00000193AF.i.24.2.Seq_THC197345 843RTA00000193AF.m.5.1.Seq_THC173318 844 RTA00000193AF.n.15.1.Seq_THC215687

Example 2 Results of Public Database Search to Identify Function of GeneProducts

SEQ ID NOS:1-404, as well as the validation sequences SEQ IDNOS:405-800, were translated in all three reading frames to determinethe best alignment with the individual sequences. These amino acidsequences and nucleotide sequences are referred, generally, as querysequences, which are aligned with the individual sequences. Query andindividual sequences were aligned using the BLAST programs, availableover the world wide web sit of the NCBI. Again the sequences were maskedto various extents to prevent searching of repetitive sequences orpoly-A sequences, using the XBLAST program for masking low complexity asdescribed above in Example 1.

Table 2 (inserted before the claims) shows the results of thealignments. Table 2 refers to each sequence by its SEQ ID NO:, theaccession numbers and descriptions of nearest neighbors from the Genbankand Non-Redundant Protein searches, and the p values of the searchresults. Table 1 identifies each SEQ ID NO: by SEQ name, clone ID, andcluster. As discussed above, a single cluster includes polynucleotidesrepresenting the same gene or gene family, and generally representssequences encoding the same gene product.

For each of SEQ ID NOS:1-800, the best alignment to a protein or DNAsequence is included in Table 2. The activity of the polypeptide encodedby SEQ ID NOS:1-800 is the same or similar to the nearest neighborreported in Table 2. The accession number of the nearest neighbor isreported, providing a reference to the activities exhibited by thenearest neighbor. The search program and database used for the alignmentalso are indicated as well as a calculation of the p value.

Full length sequences or fragments of the polynucleotide sequences ofthe nearest neighbors can be used as probes and primers to identify andisolate the full length sequence of SEQ ID NOS:1-800. The nearestneighbors can indicate a tissue or cell type to be used to construct alibrary for the full-length sequences of SEQ ID NOS:1-800.

SEQ ID NOS:1-800 and the translations thereof may be human homologs ofknown genes of other species or novel allelic variants of known humangenes. In such cases, these new human sequences are suitable asdiagnostics or therapeutics. As diagnostics, the human sequences SEQ IDNOS:1-800 exhibit greater specificity in detecting and differentiatinghuman cell lines and types than homologs of other species. The humanpolypeptides encoded by SEQ ID NOS:1-800 are likely to be lessimmunogenic when administered to humans than homologs from otherspecies. Further, on administration to humans, the polypeptides encodedby SEQ ID NOS:1-800 can show greater specificity or can be betterregulated by other human proteins than are homologs from other species.

Example 3 Members of Protein Families

After conducting a profile search as described in the specificationabove, several of the polynucleotides of the invention were found toencode polypeptides having characteristics of a polypeptide belonging toa known protein families (and thus represent new members of theseprotein families) and/or comprising a known functional domain (Table 3).Thus the invention encompasses fragments, fusions, and variants of suchpolynucleotides that retain biological activity associated with theprotein family and/or functional domain identified herein. TABLE 3Polynucleotides encoding gene products of a protein family or having aknown functional domain(s). SEQ ID NO: Biological Activity (Profile hit)Start Stop Dir 24 4 transmembrane segments integral membrane proteins1218 578 rev 41 4 transmembrane segments integral membrane proteins 1086413 rev 101 4 transmembrane segments integral membrane proteins 1206 544rev 157 4 transmembrane segments integral membrane proteins 721 33 rev341 4 transmembrane segments integral membrane proteins 1253 613 rev 3954 transmembrane segments integral membrane proteins 530 10 for 395 4transmembrane segments integral membrane proteins 696 17 for 395 4transmembrane segments integral membrane proteins 471 39 rev 24 7transmembrane receptor (Secretin family) 1301 491 rev 41 7 transmembranereceptor (Secretin family) 1309 10 rev 101 7 transmembrane receptor(Secretin family) 1330 296 rev 157 7 transmembrane receptor (Secretinfamily) 1173 249 rev 291 7 transmembrane receptor (Secretin family) 1400269 rev 291 7 transmembrane receptor (Secretin family) 712 130 for 305 7transmembrane receptor (Secretin family) 926 4 for 305 7 transmembranereceptor (Secretin family) 753 55 rev 315 7 transmembrane receptor(Secretin family) 1058 270 rev 341 7 transmembrane receptor (Secretinfamily) 1265 534 rev 116 Ank repeat 141 218 for 251 Ank repeat 290 207for 251 Ank repeat 467 387 for 63 ATPases Associated with VariousCellular Activities 543 60 for 116 ATPases Associated with VariousCellular Activities 802 313 for 134 ATPases Associated with VariousCellular Activities 525 57 rev 136 ATPases Associated with VariousCellular Activities 712 163 for 151 ATPases Associated with VariousCellular Activities 719 73 for 151 ATPases Associated with VariousCellular Activities 386 13 for 384 ATPases Associated with VariousCellular Activities 664 140 for 404 ATPases Associated with VariousCellular Activities 704 52 for 374 Basic region plus leucine zippertranscription factors 298 146 for 97 Bromodomain (conserved sequencefound in human, 230 63 for Drosophila and yeast proteins.) 136 EF-hand121 207 for 242 EF-hand 238 155 for 379 EF-hand 212 126 for 308Eukaryotic aspartyl proteases 1300 461 rev 213 GATA family oftranscription factors 720 377 for 367 G-protein alpha subunit 971 467rev 188 Phorbol esters/diacylglycerol binding 91 177 for 251 Phorbolesters/diacylglycerol binding 133 219 for 202 protein kinase 482 1 rev202 protein kinase 970 1 rev 315 protein kinase 739 158 for 315 proteinkinase 1023 197 for 367 protein kinase 1046 285 rev 397 protein kinase511 6 for 256 Protein phosphatase 2C 13 90 for 256 Protein phosphatase2C 163 86 for 382 Protein Tyrosine Phosphatase 261 2 for 306 SH3 Domain141 296 for 386 SH3 Domain 359 209 for 169 Trypsin 764 164 rev 188 WDdomain, G-beta repeats 480 382 for 188 WD domain, G-beta repeats 206 117for 335 WD domain, G-beta repeats 3 92 for 23 wnt family ofdevelopmental signaling proteins 1151 335 rev 291 wnt family ofdevelopmental signaling proteins 779 89 rev 291 wnt family ofdevelopmental signaling proteins 1347 382 rev 324 wnt family ofdevelopmental signaling proteins 1180 499 rev 330 wnt family ofdevelopmental signaling proteins 1180 499 rev 341 wnt family ofdevelopmental signaling proteins 1399 560 rev 353 wnt family ofdevelopmental signaling proteins 880 49 rev 188 WW/rsp5/WWP domaincontaining proteins 431 354 for 379 WW/rsp5/WWP domain containingproteins 12 89 for 395 WW/rsp5/WWP domain containing proteins 153 76 for395 WW/rsp5/WWP domain containing proteins 156 64 for 61 Zinc finger,C2H2 type 254 192 for 306 Zinc finger, C2H2 type 428 367 for 386 Zincfinger, C2H2 type 191 253 for 322 Zinc finger, CCHC class 553 503 for306 Zinc-binding metalloprotease domain 101 60 rev 395 Zinc-bindingmetalloprotease domain 28 69 rev

Start and stop indicate the position within the individual sequenes thatalign with the query sequence having the indicated SEQ ID NO. Thedirection (Dir) indicates the orientation of the query sequence withrespect to the individual sequence, where forward (for) indicates thatthe alignment is in the same direction (left to right) as the sequenceprovided in the Sequence Listing and reverse (rev) indicates that thealignment is with a sequence complementary to the sequence provided inthe Sequence Listing. Some polynucleotides exhibited multiple profilehits because, for example, the particular sequence contains overlappingprofile regions, and/or the sequence contains two different functionaldomains. These profile hits are described in more detail below.

a) Four Transmembrane Integral Membrane Proteins. SEQ ID NOS: 24, 41,101, 157, 341, and 395 correspond to a sequence encoding a polypeptidethat is a member of the 4 transmembrane segments integral membraneprotein family (transmembrane 4 family). The transmembrane 4 family ofproteins includes a number of evolutionarily-related eukaryotic cellsurface antigens (Levy et al., J. Biol. Chem., (1991) 266:14597;Tomlinson et al., Eur. J. Immunol. (1993) 23:136; Barclay et al. Theleucocyte antigen factbooks. (1993) Academic Press, London/San Diego).The proteins belonging to this family include: 1) Mammalian antigen CD9(MIC3), which is involved in platelet activation and aggregation; 2)Mammalian leukocyte antigen CD37, expressed on B lymphocytes; 3)Mammalian leukocyte antigen CD53 (OX-44), which is implicated in growthregulation in hematopoietic cells; 4) Mammalian lysosomal membraneprotein CD63 (melanoma-associated antigen ME491; antigen AD1); 5)Mammalian antigen CD81 (cell surface protein TAPA-1), which isimplicated in regulation of lymphoma cell growth; 6) Mammalian antigenCD82 (protein R2; antigen C33; Kangai 1 (KAI1)), which associates withCD4 or CD8 and delivers costimulatory signals for the TCR/CD3 pathway;7) Mammalian antigen CD151 (SFA-1; platelet-endothelial tetraspanantigen 3 (PETA-3)); 8) Mammalian cell surface glycoprotein A15(TALLA-1; MXS1); 9) Mammalian novel antigen 2 (NAG-2); 10) Humantumor-associated antigen CO-029; 11) Schistosoma mansoni and japonicum23 Kd surface antigen (SM23/SJ23).

The members of the 4 transmembrane family share several characteristics.First, they all are apparently type III membrane proteins, which areintegral membrane proteins containing an N-terminal membrane-anchoringdomain which is not cleaved during biosynthesis and which functions bothas a translocation signal and as a membrane anchor. The family membersalso contain three additional transmembrane regions, at least sevenconserved cysteines residues, and are of approximately the same size(218 to 284 residues). These proteins are collectively know as the“transmembrane 4 superfamily” (TM4) because they span plasma membranefour times. A schematic diagram of the domain structure of theseproteins is as follows:

where Cyt is the cytoplasmic domain, TMa is the transmembrane anchor;TM2 to TM4 represents transmembrane regions 2 to 4, ‘C’ are conservedcysteines, and ‘*’ indicates the position of the consensus pattern. Theconsensus pattern spans a conserved region including two cysteineslocated in a short cytoplasmic loop between two transmembrane domains:Consensus pattern:G-x(3)-[LIVMF]-x(2)-[GSA]-[LIVMF](2)-G-C-x-[GA]-[STA]-x(2)-[EG]-x(2)-[CWN]-[LIVM](2).

b) Seven Transmembrane Integral Membrane Proteins. SEQ ID NOS: 24, 41,101, 157, 291, 305, 315, and 341 correspond to a sequence encoding apolypeptide that is a member of the seven transmembrane receptor family.G-protein coupled receptors (Strosberg, Eur. J. Biochem. (1991) 196:1;Kerlavage, Curr. Opin. Struct. Biol. (1991) 1:394; and Probst et al.,DNA Cell Biol. (1992) 11:1; and Savarese et al., Biochem. J. (1992)293:1) (also called R7G) are an extensive group of hormones,neurotransmitters, odorants and light receptors which transduceextracellular signals by interaction with guanine nucleotide-binding (G)proteins. The tertiary structure of these receptors is thought to behighly similar. They have seven hydrophobic regions, each of which mostprobably spans the membrane. The N-terminus is located on theextracellular side of the membrane and is often glycosylated, while theC-terminus is cytoplasmic and generally phosphorylated. Threeextracellular loops alternate with three intracellular loops to link theseven transmembrane regions. Most, but not all of these receptors, lacka signal peptide. The most conserved parts of these proteins are thetransmembrane regions and the first two cytoplasmic loops. A conservedacidic-Arg-aromatic triplet is present in the N-terminal extremity ofthe second cytoplasmic loop (Attwood et al., Gene (1991) 98:153) andcould be implicated in the interaction with G proteins.

To detect this widespread family of proteins a pattern is used thatcontains the conserved triplet and that also spans the major part of thethird transmembrane helix. Additional information about the seventransmembrane receptor family, and methods for their identification anduse, is found in U.S. Pat. No. 5,759,804. Due in part to theirexpression on the cell surface and other attractive characteristics,seven transmembrane protein family members are of particular interest asdrug targets, as surface antigen markers, and as drug delivery targets(e.g., using antibody-drug complexes and/or use of anti-seventransmembrane protein antibodies as therapeutics in their own right).

c) Ank Repeats. SEQ ID NOS: 116 and 251 represent polynucleotidesencoding Ank repeat-containing proteins. The ankyrin motif is a 33 aminoacid sequence named after the protein ankyrin which has 24 tandem33-amino-acid motifs. Ank repeats were originally identified in thecell-cycle-control protein cdc10 (Breeden et al., Nature (1987)329:651). Proteins containing ankyrin repeats include ankyrin,myotropin, I-kappaB proteins, cell cycle protein cdc10, the Notchreceptor (Matsuno et al., Development (1997) 124(21):4265); G9a (orBAT8) of the class III region of the major histocompatibility complex(Biochem J. 290:811-818, 1993), FABP, GABP, 53BP2, Lin12, glp-1, SW14,and SW16. The functions of the ankyrin repeats are compatible with arole in protein-protein interactions (Bork, Proteins (1993) 17(4):363;Lambert and Bennet, Eur. J. Biochem. (1993) 211:1; Kerr et al., CurrentOp. Cell Biol. (1992) 4:496; Bennet et al., J. Biol. Chem. (1980)255:6424).

The 90 kD N-terminal domain of ankyrin contains a series of 2433-amino-acid ank repeats. (Lux et al., Nature (1990) 344:36-42, Lambertet al., PNAS USA (1990) 87:1730.) The 24 ank repeats form four foldedsubdomains of 6 repeats each. These four repeat subdomains mediateinteractions with at least 7 different families of membrane proteins.Ankyrin contains two separate binding sites for anion exchanger dimers.One site utilizes repeat subdomain two (repeats 7-12) and the otherrequires both repeat subdomains 3 and 4 (repeats 13-24). Since the anionexchangers exist in dimers, ankyrin binds 4 anion exchangers at the sametime. (Michaely and Bennett, J. Biol. Chem. (1995) 270(37):22050) Therepeat motifs are involved in ankyrin interaction with tubulin,spectrin, and other membrane proteins. (Lux et al., Nature (1990)344:36.)

The Rel/NF-kappaB/Dorsal family of transcription factors have activitythat is controlled by sequestration in the cytoplasm in association withinhibitory proteins referred to as I-kappaB. (Gilmore, Cell (1990)62:841; Nolan and Baltimore, Curr Opin Genet Dev. (1992) 2:211;Baeuerle, Biochim Biophys Acta (1991) 1072:63; Schmitz et al., TrendsCell Biol. (1991) 1:130.) I-kappaB proteins contain 5 to 8 copies of 33amino acid ankyrin repeats and certain NF-kappaB/rel proteins are alsoregulated by cis-acting ankyrin repeat containing domains includingp105NF-kappaB which contains a series of ankyrin repeats (Diehl andHannink, J. Virol. (1993) 67(12):7161). The I-kappaBs and Cactus (alsocontaining ankyrin repeats) inhibit activators through differentialinteractions with the Rel-homology domain. The gene family includesproto-oncogenes, thus broadly implicating I-kappaB in the control ofboth normal gene expression and the aberrant gene expression that makescells cancerous. (Nolan and Baltimore, Curr Opin Genet Dev. (1992)2(2):211-220). In the case of rel/NF-kappaB and pp40/I-kappaBβ, both theankyrin repeats and the carboxy-terminal domain are required forinhibiting DNA-binding activity and direct association of pp40/I-kappaBβwith rel/NF-kappaB protein. The ankyrin repeats and the carboxy-terminalof pp40/I-kappaBβ (form a structure that associates with the relhomology domain to inhibit DNA binding activity (Inoue et al., PNAS USA(1992) 89:4333).

The 4 ankyrin repeats in the amino terminus of the transcription factorsubunit GABPβ are required for its interaction with the GABPα subunit toform a functional high affinity DNA-binding protein. These repeats canbe crosslinked to DNA when GABP is bound to its target sequence.(Thompson et al., Science (1991) 253:762; LaMarco et al., Science (1991)253:789).

Myotrophin, a 12.5 kDa protein having a key role in the initiation ofcardiac hypertrophy, comprises ankyrin repeats. The ankyrin repeats arecharacteristic of a hairpin-like protruding tip followed by ahelix-turn-helix motif. The V-shaped helix-turn-helix of the repeatsstack sequentially in bundles and are stabilized by compact hydrophobiccores, whereas the protruding tips are less ordered.

d) ATPases Associated with Various Cellular Activities (AAA). SEQ IDNOS: 63, 116, 134, 136, 151, 384, and 404 polynucleotides encoding novelmembers of the “ATPases Associated with diverse cellular Activities”(AAA) protein family The AAA protein family is composed of a largenumber of ATPases that share a conserved region of about 220 amino acidsthat contains an ATP-binding site (Froehlich et al., J. Cell Biol.(1991) 114:443; Erdmann et al. Cell (1991) 64:499; Peters et al., EMBOJ. (1990) 9:1757; Kunau et al., Biochimie (1993) 75:209-224;Confalonieri et al., BioEssays (1995) 17:639;http://yeamob.pci.chemie.uni-tuebingen.de/AAA/Description.html). Theproteins that belong to this family either contain one or two AAAdomains.

Proteins containing two AAA domains include: 1) Mammalian and drosophilaNSF (N-ethylmaleimide-sensitive fusion protein) and the fungal homolog,SEC18, which are involved in intracellular transport between theendoplasmic reticulum and Golgi, as well as between different Golgicisternae; 2) Mammalian transitional endoplasmic reticulum ATPase(previously known as p97 or VCP), which is involved in the transfer ofmembranes from the endoplasmic reticulum to the golgi apparatus. ThisATPase forms a ring-shaped homooligomer composed of six subunits. Theyeast homolog, CDC48, plays a role in spindle pole proliferation; 3)Yeast protein PAS1 essential for peroxisome assembly and the relatedprotein PAS1 from Pichia pastoris; 4) Yeast protein AFG2; 5) Sulfolobusacidocaldarius protein SAV and Halobacterium salinarium cdcH; which maybe part of a transduction pathway connecting light to cell division.

Proteins containing a single AAA domain include: 1) Escherichia coli andother bacteria ftsH (or hflB) protein. FtsH is an ATP-dependent zincmetallopeptidase that degrades the heat-shock sigma-32 factor, and is anintegral membrane protein with a large cytoplasmic C-terminal domainthat contain both the AAA and the protease domains; 2) Yeast proteinYME1, a protein important for maintaining the integrity of themitochondrial compartment. YME1 is also a zinc-dependent protease; 3)Yeast protein AFG3 (or YTA10). This protein also contains an AAA domainfollowed by a zinc-dependent protease domain; 4) Subunits fromregulatory complex of the 26S proteasome (Hilt et al., Trends Biochem.Sci. (1996) 21:96), which is involved in the ATP-dependent degradationof ubiquitinated proteins, which subunits include: a) Mammalian 4 andhomologs in other higher eukaryotes, in yeast (gene YTA5) and fissionyeast (gene mts2); b) Mammalian 6 (TBP7) and homologs in other highereukaryotes and in yeast (gene YTA2); c) Mammalian subunit 7 (MSS1) andhomologs in other higher eukaryotes and in yeast (gene CIM5 or YTA3); d)Mammalian subunit 8 (P45) and homologs in other higher eukaryotes and inyeast (SUG1 or CIM3 or TBY1) and fission yeast (gene let1); e) Otherprobable subunits include human TBP1, which influences HIV geneexpression by interacting with the virus tat transactivator protein, andyeast YTA1 and YTA6; 5) Yeast protein BCS1, a mitochondrial proteinessential for the expression of the Rieske iron-sulfur protein; 6) Yeastprotein MSP1, a protein involved in intramitochondrial sorting ofproteins; 7) Yeast protein PAS8, and the corresponding proteins PAS5from Pichia pastoris and PAY4 from Yarrowia lipolytica; 8) Mouse proteinSKD1 and its fission yeast homolog (SpAC2G11.06); 9) Caenorhabditiselegans meiotic spindle formation protein mei-1; 10) Yeast protein SAP1′11) Yeast protein YTA7; and 12) Mycobacterium leprae hypotheticalprotein A2126A.

In general, the AAA domains in these proteins act as ATP-dependentprotein clamps (Confalonieri et al. (1995) BioEssays 17:639). Inaddition to the ATP-binding ‘A’ and ‘B’ motifs, which are located in theN-terminal half of this domain, there is a highly conserved regionlocated in the central part of the domain which was used in thedevelopment of the signature pattern.

e) Basic Region Plus Leucine Zipper Transcription Factors. SEQ ID NO:374correspond to a polynucleotide encoding a novel member of the family ofbasic region plus leucine zipper transcription factors. The bZIPsuperfamily (Hurst, Protein Prof. (1995) 2:105; and Ellenberger, Curr.Opin. Struct. Biol. (1994) 4:12) of eukaryotic DNA-binding transcriptionfactors encompasses proteins that contain a basic region mediatingsequence-specific DNA-binding followed by a leucine zipper required fordimerization. Members of the family include transcription factor AP-1,which binds selectively to enhancer elements in the cis control regionsof SV40 and metallothionein IIA. AP-1, also known as c-jun, is thecellular homolog of the avian sarcoma virus 17 (ASV17) oncogene v-jun.

Other members of this protein family include jun-B and jun-D, probabletranscription factors that are highly similar to jun/AP-1; the fosprotein, a proto-oncogene that forms a non-covalent dimer with c-jun;the fos-related proteins fra-1, and fos B; and mammalian cAMP responseelement (CRE) binding proteins CREB, CREM, ATF-1, ATF-3, ATF-4, ATF-5,ATF-6 and LRF-1.

f) Bromodomain. SEQ ID NO:97 corresponds to a polynucleotide encoding apolypeptide having a bromodomain region (Haynes et al., 1992, NucleicAcids Res. 20:2693-2603, Tamkun et al., 1992, Cell 68:561-572, andTamkun, 1995, Curr. Opin. Genet. Dev. 5:473-477), which is a conservedregion of about 70 amino acids found in the following proteins: 1)Higher eukaryotes transcription initiation factor TFIID 250 Kd subunit(TBP-associated factor p250) (gene CCG1); P250 is associated with theTFIID TATA-box binding protein and seems essential for progression ofthe G1 phase of the cell cycle. 2) Human RING3, a protein of unknownfunction encoded in the MHC class II locus; 3) Mammalian CREB-bindingprotein (CBP), which mediates cAMP-gene regulation by bindingspecifically to phosphorylated CREB protein; 4) Mammalian homologs ofbrahma, including three brahma-like human: SNF2a(hBRM), SNF2b, and BRG1;5) Human BS69, a protein that binds to adenovirus E1A and inhibits E1Atransactivation; 6) Human peregrin (or Br140).

The bromodomain is thought to be involved in protein-proteininteractions and may be important for the assembly or activity ofmulticomponent complexes involved in transcriptional activation.

g) EF-Hand. SEQ ID NOS:136, 242, and 379 correspond to polynucleotidesencoding a novel protein in the family of EF-hand proteins. Manycalcium-binding proteins belong to the same evolutionary family andshare a type of calcium-binding domain known as the EF-hand (Kawasaki etal., Protein. Prof. (1995) 2:305-490). This type of domain consists of atwelve residue loop flanked on both sides by a twelve residuealpha-helical domain. In an EF-hand loop the calcium ion is coordinatedin a pentagonal bipyramidal configuration. The six residues involved inthe binding are in positions 1, 3, 5, 7, 9 and 12; these residues aredenoted by X, Y, Z, −Y, −X and −Z. The invariant Glu or Asp at position12 provides two oxygens for liganding Ca (bidentate ligand).

Proteins known to contain EF-hand regions include: Calmodulin (Ca=4,except in yeast where Ca=3) (“Ca=” indicates approximate number ofEF-hand regions); diacylglycerol kinase (EC 2.7.1.107) (DGK) (Ca=2); 2)FAD-dependent glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) frommammals (Ca=1); guanylate cyclase activating protein (GCAP) (Ca=3); MIFrelated proteins 8 (MRP-8 or CFAG) and 14 (MRP-14) (Ca=2); myosinregulatory light chains (Ca=1); oncomodulin (Ca=2); osteonectin(basement membrane protein BM-40) (SPARC); and proteins that contain an“osteonectin” domain (QR1, matrix glycoprotein SC1).

The consensus pattern includes the complete EF-hand loop as well as thefirst residue which follows the loop and which seem to always behydrophobic.

h) Eukaryotic Aspartyl Proteases. SEQ ID NO:308 corresponds to a geneencoding a novel eukaryotic aspartyl protease. Aspartyl proteases, knownas acid proteases, (EC 3.4.23.-) are a widely distributed family ofproteolytic enzymes (Foltmann B., Essays Biochem. (1981) 17:52; DaviesD. R., Annu. Rev. Biophys. Chem. (1990) 19:189; Rao J. K. M., et al.,Biochemistry (1991) 30:4663) known to exist in vertebrates, fungi,plants, retroviruses and some plant viruses. Aspartate proteases ofeukaryotes are monomeric enzymes which consist of two domains. Eachdomain contains an active site centered on a catalytic aspartyl residue.The two domains most probably evolved from the duplication of anancestral gene encoding a primordial domain. Currently known eukaryoticaspartyl proteases include: 1) Vertebrate gastric pepsins A and C (alsoknown as gastricsin); 2) Vertebrate chymosin (rennin), involved indigestion and used for making cheese; 3) Vertebrate lysosomal cathepsinsD (EC 3.4.23.5) and E (EC 3.4.23.34); 4) Mammalian renin (EC 3.4.23.15)whose function is to generate angiotensin I from angiotensinogen in theplasma; 5) Fungal proteases such as aspergillopepsin A (EC 3.4.23.18),candidapepsin (EC 3.4.23.24), mucoropepsin (EC 3.4.23.23) (mucorrennin), endothiapepsin (EC 3.4.23.22), polyporopepsin (EC 3.4.23.29),and rhizopuspepsin (EC 3.4.23.21); and 6) Yeast saccharopepsin (EC3.4.23.25) (proteinase A) (gene PEP4). PEP4 is implicated inposttranslational regulation of vacuolar hydrolases; 7) Yeastbarrierpepsin (EC 3.4.23.35) (gene BAR1); a protease that cleavesalpha-factor and thus acts as an antagonist of the mating pheromone; and8) Fission yeast sxa1 which is involved in degrading or processing themating pheromones.

Most retroviruses and some plant viruses, such as badnaviruses, encodefor an aspartyl protease which is an homodimer of a chain of about 95 to125 amino acids. In most retroviruses, the protease is encoded as asegment of a polyprotein which is cleaved during the maturation processof the virus. It is generally part of the pol polyprotein and, morerarely, of the gag polyprotein. Because the sequence around the twoaspartates of eukaryotic aspartyl proteases and around the single activesite of the viral proteases is conserved, a single signature pattern canbe used to identify members of both groups of proteases.

i) GATA Family of Transcription Factors. SEQ ID NO:213 corresponds to anovel member of the GATA family of transcription factors. The GATAfamily of transcription factors are proteins that bind to DNA sites withthe consensus sequence (A/T)GATA(A/G), found within the regulatoryregion of a number of genes. Proteins currently known to belong to thisfamily are: 1) GATA-1 (Trainor, C. D., et al., Nature (1990) 343:92)(also known as Eryf1, GF-1 or NF-E1), which binds to the GATA region ofglobin genes and other genes expressed in erythroid cells. It is atranscriptional activator which probably serves as a general ‘switch’factor for erythroid development; 2) GATA-2 (Lee, M. E., et al., J.Biol. Chem. (1991) 266:16188), a transcriptional activator whichregulates endothelin-1 gene expression in endothelial cells; 3) GATA-3(Ho, I. -C., et al., EMBO J. (1991) 10:1187), a transcriptionalactivator which binds to the enhancer of the T-cell receptor alpha anddelta genes; 4) GATA-4 (Spieth, J., et al., Mol. Cell. Biol. (1991)11:4651), a transcriptional activator expressed in endodermally derivedtissues and heart; 5) Drosophila protein pannier (or DGATAa) (gene pnr)which acts as a repressor of the achaete-scute complex (as-c); 6) Bombyxmori BCFI (Drevet, J. R., et al., J. Biol. Chem. (1994) 269:10660),which regulates the expression of chorion genes; 7) Caenorhabditiselegans elt-1 and elt-2, transcriptional activators of genes containingthe GATA region, including vitellogenin genes (Hawkins, M. G., et al.,J. Biol. Chem. (1995) 270:14666); 8) Ustilago maydis urbs1 (Voisard, C.P. O., et al., Mol. Cell. Biol. (1993) 13:7091), a protein involved inthe repression of the biosynthesis of siderophores; 9) Fission yeastprotein GAF2.

All these transcription factors contain a pair of highly similar ‘zincfinger’ type domains with the consensus sequence C-x2-C-x17-C-x2-C. Someother proteins contain a single zinc finger motif highly related tothose of the GATA transcription factors. These proteins are: 1)Drosophila box A-binding factor (ABF) (also known as protein serpent(gene srp)) which may function as a transcriptional activator proteinand may play a key role in the organogenesis of the fat body; 2)Emericella nidulans are (Arst, H. N., Jr., et al., Trends Genet. (1989)5:291) a transcriptional activator which mediates nitrogen metaboliterepression; 3) Neurospora crassa nit-2 (Fu, Y. -H., et al., Mol. Cell.Biol. (1990) 10:1056), a transcriptional activator which turns on theexpression of genes coding for enzymes required for the use of a varietyof secondary nitrogen sources, during conditions of nitrogen limitation;4) Neurospora crassa white collar proteins 1 and 2 (WC-1 and WC-2),which control expression of light-regulated genes; 5) Saccharomycescerevisiae DAL81 (or UGA43), a negative nitrogen regulatory protein; 6)Saccharomyces cerevisiae GLN3, a positive nitrogen regulatory protein;7) Saccharomyces cerevisiae GAT1; 8) Saccharomyces cerevisiae GZF3.

j) G-Protein Alpha Subunit. SEQ ID NO:367 corresponds to a gene encodinga novel polypeptide of the G-protein alpha subunit family. Guaninenucleotide binding proteins (G-proteins) are a family ofmembrane-associated proteins that couple extracellularly-activatedintegral-membrane receptors to intracellular effectors, such as ionchannels and enzymes that vary the concentration of second messengermolecules. G-proteins are composed of 3 subunits (alpha, beta and gamma)which, in the resting state, associate as a trimer at the inner face ofthe plasma membrane. The alpha subunit has a molecule of guanosinediphosphate (GDP) bound to it. Stimulation of the G-protein by anactivated receptor leads to its exchange for GTP (guanosinetriphosphate). This results in the separation of the alpha from the betaand gamma subunits, which always remain tightly associated as a dimer.Both the alpha and beta-gamma subunits are then able to interact witheffectors, either individually or in a cooperative manner. The intrinsicGTPase activity of the alpha subunit hydrolyses the bound GTP to GDP.This returns the alpha subunit to its inactive conformation and allowsit to reassociate with the beta-gamma subunit, thus restoring the systemto its resting state.

G-protein alpha subunits are 350-400 amino acids in length and havemolecular weights in the range 40-45 kDa. Seventeen distinct types ofalpha subunit have been identified in mammals. These fall into 4 maingroups on the basis of both sequence similarity and function: alpha-s,alpha-q, alpha-i and alpha-12 (Simon et al., Science (1993) 252:802).Many alpha subunits are substrates for ADP-ribosylation by cholera orpertussis toxins. They are often N-terminally acylated, usually withmyristate and/or palmitoylate, and these fatty acid modifications areprobably important for membrane association and high-affinityinteractions with other proteins. The atomic structure of the alphasubunit of the G-protein involved in mammalian vision, transducin, hasbeen elucidated in both GTP- and GDB-bound forms, and shows considerablesimilarity in both primary and tertiary structure in thenucleotide-binding regions to other guanine nucleotide binding proteins,such as p21-ras and EF-Tu.

k) Phorbol Esters/Diacylglycerol Binding. SEQ ID NO:188 and 251represent polynucleotides encoding a protein belonging to the familyincluding phorbol esters/diacylglycerol binding proteins. Diacylglycerol(DAG) is an important second messenger. Phorbol esters (PE) areanalogues of DAG and potent tumor promoters that cause a variety ofphysiological changes when administered to both cells and tissues. DAGactivates a family of serine/threonine protein kinases, collectivelyknown as protein kinase C (PKC) (Azzi et al., Eur. J. Biochem. (1992)208:547). Phorbol esters can directly stimulate PKC. The N-terminalregion of PKC, known as C1, has been shown (Ono et al., Proc. Natl.Acad. Sci. USA (1989) 86:4868) to bind PE and DAG in a phospholipid andzinc-dependent fashion. The C1 region contains one or two copies(depending on the isozyme of PKC) of a cysteine-rich domain about 50amino-acid residues long and essential for DAG/PE-binding. Such a domainhas also been found in, for example, the following proteins.

(1) Diacylglycerol kinase (EC 2.7.1.107) (DGK) (Sakane et al., Nature(1990) 344:345), the enzyme that converts DAG into phosphatidate. Itcontains two copies of the DAG/PE-binding domain in its N-terminalsection. At least five different forms of DGK are known in mammals; and

(2) N-chimaerin, a brain specific protein which shows sequencesimilarities with the BCR protein at its C-terminal part and contains asingle copy of the DAG/PE-binding domain at its N-terminal part. It hasbeen shown (Ahmed et al., Biochem. J. (1990) 272:767, and Ahmed et al.,Biochem. J. (1991) 280:233) to be able to bind phorbol esters.

The DAG/PE-binding domain binds two zinc ions; the ligands of thesemetal ions are probably the six cysteines and two histidines that areconserved in this domain. The signature pattern completely spans theDAG/PE domain. The consensus pattern is:H-x-[LIVMFYW]-x(8,11)-C-x(2)-C-x(3)-[LIVMFC]-x(5,10)-C-x(2)-C-x(4)-[HD]-x(2)-C-x(5,9)-C.All the C and H are probably involved in binding zinc.

l) Protein Kinase. SEQ ID NOS:202, 315, 367, and 397 representpolynucleotides encoding protein kinases. Protein kinases catalyzephosphorylation of proteins in a variety of pathways, and are implicatedin cancer. Eukaryotic protein kinases (Hanks S. K., et al., FASEB J.(1995) 9:576; Hunter T., Meth. Enzymol. (1991) 200:3; Hanks S. K., etal., Meth. Enzymol. (1991) 200:38; Hanks S. K., Curr. Opin. Struct.Biol. (1991) 1:369; Hanks S. K., et al., Science (1988) 241:42) areenzymes that belong to a very extensive family of proteins which share aconserved catalytic core common to both serine/threonine and tyrosineprotein kinases. There are a number of conserved regions in thecatalytic domain of protein kinases. Two of the conserved regions arethe basis for the signature pattern in the protein kinase profile. Thefirst region, which is located in the N-terminal extremity of thecatalytic domain, is a glycine-rich stretch of residues in the vicinityof a lysine residue, which has been shown to be involved in ATP binding.The second region, which is located in the central part of the catalyticdomain, contains a conserved aspartic acid residue which is importantfor the catalytic activity of the enzyme (Knighton D. R., et al.,Science (1991) 253:407). The protein kinase profile includes twosignature patterns for this second region: one specific forserine/threonine kinases and the other for tyrosine kinases. A thirdprofile is based on the alignment in (Hanks S. K., et al., FASEB J.(1995) 9:576) and covers the entire catalytic domain.

The protein kinase profile also detects receptor guanylate cyclases and2-5A-dependent ribonucleases. Sequence similarities between these twofamilies and the eukaryotic protein kinase family have been noticedpreviously. The profile also detects Arabidopsis thaliana kinase-likeprotein TMKL1 which seems to have lost its catalytic activity.

If a protein analyzed includes the two of the above protein kinasesignatures, the probability of it being a protein kinase is close to100%. Eukaryotic-type protein kinases have also been found inprokaryotes such as Myxococcus xanthus (Munoz-Dorado J., et al, Cell(1991) 67:995) and Yersinia pseudotuberculosis. The patterns shown abovehas been updated since their publication in (Bairoch A., et al., Nature(1988) 331:22).

m) Protein Phosphatase 2C, SEQ ID NO:256 corresponds to a polynucleotideencoding a novel protein phosphatase 2C (PP2C), which is one of the fourmajor classes of mammalian serine/threonine specific proteinphosphatases. PP2C (Wenk et al., FEBS Lett. (1992) 297:135) is amonomeric enzyme of about 42 Kd which shows broad substrate specificityand is dependent on divalent cations (mainly manganese and magnesium)for its activity. Three isozymes are currently known in mammals:PP2C-alpha, -beta and -gamma.

n) Protein Tyrosine Phosphatase. SEQ ID NO:382 represents apolynucleotide encoding a protein tyrosine kinase. Tyrosine specificprotein phosphatases (EC 3.1.3.48) (PTPase) (Fischer et al., Science(1991) 253:401; Charbonneau et al., Annu. Rev. Cell Biol. (1992) 8:463;Trowbridge, J. Biol. Chem. (1991) 266:23517; Tonks et al., TrendsBiochem. Sci. (1989) 14:497; and Hunter, Cell (1989) 58:1013) catalyzethe removal of a phosphate group attached to a tyrosine residue. Theseenzymes are very important in the control of cell growth, proliferation,differentiation and transformation. Multiple forms of PTPase have beencharacterized and can be classified into two categories: soluble PTPasesand transmembrane receptor proteins that contain PTPase domain(s).

Soluble PTPases include PTPN3 (H1) and PTPN4 (MEG), enzymes that containan N-terminal band 4.1-like domain and could act at junctions betweenthe membrane and cytoskeleton; PTPN6 (PTP-1C; HCP; SHP) and PTPN11(PTP-2C; SH-PTP3; Syp), enzymes that contain two copies of the SH2domain at its N-terminal extremity.

Dual specificity PTPases include DUSP1 (PTPN10; MAP kinasephosphatase-1; MKP-1) which dephosphorylates MAP kinase on both Thr-183and Tyr-185; and DUSP2 (PAC-1), a nuclear enzyme that dephosphorylatesMAP kinases ERK1 and ERK2 on both Thr and Tyr residues.

Structurally, all known receptor PTPases are made up of a variablelength extracellular domain, followed by a transmembrane region and aC-terminal catalytic cytoplasmic domain. Some of the receptor PTPasescontain fibronectin type III (FN-III) repeats, immunoglobulin-likedomains, MAM domains or carbonic anhydrase-like domains in theirextracellular region. The cytoplasmic region generally contains twocopies of the PTPAse domain. The first seems to have enzymatic activity,while the second is inactive but seems to affect substrate specificityof the first. In these domains, the catalytic cysteine is generallyconserved but some other, presumably important, residues are not.

PTPase domains consist of about 300 amino acids. There are two conservedcysteines and the second one has been shown to be absolutely requiredfor activity. Furthermore, a number of conserved residues in itsimmediate vicinity have also been shown to be important. The consensuspattern for PTPases is:[LIVMF]-H-C-x(2)-G-x(3)-[STC]-[STAGP]-x-[LIVMFY]; C is the active siteresidue.

o) SH3 Domain. SEQ ID NO:306 and 386 represent polynucleotides encodingSH3 domain proteins. The Src homology 3 (SH3) domain is a small proteindomain of about 60 amino acid residues first identified as a conservedsequence in the non-catalytic part of several cytoplasmic proteintyrosine kinases (e.g. Src, Abl, Lck) (Mayer et al., Nature (1988)332:272). The domain has also been found in a variety of intracellularor membrane-associated proteins (Musacchio et al., FEBS Lett. (1992)307:55; Pawson et al., Curr. Biol. (1993) 3:434; Mayer et al., TrendsCell Biol. (1993) 3:8; and Pawson et al., Nature (1995) 373:573).

The SH3 domain has a characteristic fold that consists of five or sixbeta-strands arranged as two tightly packed anti-parallel beta sheets.The linker regions may contain short helices (Kuriyan et al., Curr.Opin. Struct. Biol. (1993) 3:828). It is believed that SH3domain-containing proteins mediate assembly of specific proteincomplexes via binding to proline-rich peptides (Morton et al., Curr.Biol. (1994) 4:615). In general, SH3 domains are found as single copiesin a given protein, but there is a significant number of proteins withtwo SH3 domains and a few with 3 or 4 copies.

SH3 domains have been identified in, for example, protein tyrosinekinases, such as the Src, Abl, Bkt, Csk and ZAP70 families of kinases;mammalian phosphatidylinositol-specific phospholipase C-gamma-1 and -2;mammalian phosphatidyl inositol 3-kinase regulatory p85 subunit;mammalian Ras GTPase-activating protein (GAP); mammalian Vavoncoprotein, a guanine nucleotide exchange factor of the CDC24 family;Drosophila lethal(1)discs large-1 tumor suppressor protein (gene Dlg1);mammalian tight junction protein ZO-1; vertebrate erythrocyte membraneprotein p55; Caenorhabditis elegans protein lin-2; rat protein CASK; andmammalian synaptic proteins SAP90/PSD-95, CHAPSYN-110/PSD-93, SAP97/DLG1and SAP102. Novel SH3-domain containing polypeptides will facilitateelucidation of the role of such proteins in important biologicalpathways, such as ras activation.

p) Trypsin. SEQ ID NO:169 corresponds to a novel serine protease of thetrypsin family. The catalytic activity of the serine proteases from thetrypsin family is provided by a charge relay system involving anaspartic acid residue hydrogen-bonded to a histidine, which itself ishydrogen-bonded to a serine. The sequences in the vicinity of the activesite serine and histidine residues are well conserved in this family ofproteases (Brenner S., Nature (1988) 334:528). Proteases known to belongto the trypsin family include: 1) Acrosin; 2) Blood coagulation factorsVII, IX, X, XI and XII, thrombin, plasminogen, and protein C; 3)Cathepsin G; 4) Chymotrypsins; 5) Complement components C1r, C1s, C2,and complement factors B, D and I; 6) Complement-activating component ofRA-reactive factor; 7) Cytotoxic cell proteases (granzymes A to H); 8)Duodenase I; 9) Elastases 1, 2, 3A, 3B (protease E), leukocyte(medullasin); 10) Enterokinase (EC 3.4.21.9) (enteropeptidase); 11)Hepatocyte growth factor activator; 12) Hepsin; 13) Glandular (tissue)kallikreins (including EGF-binding protein types A, B, and C, NGF-gammachain, gamma-renin, prostate specific antigen (PSA) and tonin); 14)Plasma kallikrein; 15) Mast cell proteases (MCP) 1 (chymase) to 8; 16)Myeloblastin (proteinase 3) (Wegener's autoantigen); 17) Plasminogenactivators (urokinase-type, and tissue-type); 18) Trypsins I, II, III,and IV; 19) Tryptases; 20) Snake venom proteases such as ancrod,batroxobin, cerastobin, flavoxobin, and protein C activator; 21)Collagenase from common cattle grub and collagenolytic protease fromAtlantic sand fiddler crab; 22) Apolipoprotein(a); 23) Blood flukecercarial protease; 24) Drosophila trypsin like proteases: alpha,easter, snake-locus; 25) Drosophila protease stubble (gene sb); and 26)Major mite fecal allergen Der p III. All the above proteins belong tofamily S1 in the classification of peptidases (Rawlings N. D., et al.,Meth. Enzymol. (1994) 244:19;http://www.expasy.ch/cgi-bin/lists?peptidas.txt) and originate fromeukaryotic species. It should be noted that bacterial proteases thatbelong to family S2A are similar enough in the regions of the activesite residues that they can be picked up by the same patterns.

q) WD Domain, G-Beta Repeats. SEQ ID NOS:188 and 335 represent novelmembers of the WD domain/G-beta repeat family. Beta-transducin (G-beta)is one of the three subunits (alpha, beta, and gamma) of the guaninenucleotide-binding proteins (G proteins) which act as intermediaries inthe transduction of signals generated by transmembrane receptors(Gilman, Annu. Rev. Biochem. (1987) 56:615). The alpha subunit binds toand hydrolyzes GTP; the functions of the beta and gamma subunits areless clear but they seem to be required for the replacement of GDP byGTP as well as for membrane anchoring and receptor recognition.

In higher eukaryotes, G-beta exists as a small multigene family ofhighly conserved proteins of about 340 amino acid residues.Structurally, G-beta consists of eight tandem repeats of about 40residues, each containing a central Trp-Asp motif (this type of repeatis sometimes called a WD-40 repeat). Such a repetitive segment has beenshown to exist in a number of other proteins including: human LIS1, aneuronal protein involved in type-1 lissencephaly; and mammaliancoatomer beta′ subunit (beta′-COP), a component of a cytosolic proteincomplex that reversibly associates with Golgi membranes to form vesiclesthat mediate biosynthetic protein transport.

r) wnt Family of Developmental Signaling Proteins. SEQ ID NO: 23, 291,324, 330, 341, and 353 correspond to novel members of the wnt family ofdevelopmental signaling proteins. Wnt-1 (previously known as int-1), theseminal member of this family, (Nusse R., Trends Genet. (1988) 4:291) isa proto-oncogene induced by the integration of the mouse mammary tumorvirus. It is thought to play a role in intercellular communication andseems to be a signalling molecule important in the development of thecentral nervous system (CNS). The sequence of wnt-1 is highly conservedin mammals, fish, and amphibians. Wnt-1 was found to be a member of alarge family of related proteins (Nusse R., et al., Cell (1992) 69:1073;McMahon A. P., Trends Genet. (1992) 8:1; Moon R. T., BioEssays (1993)15:91) that are all thought to be developmental regulators. Theseproteins are known as wnt-2 (also known as irp), wnt-3, -3A, -4, -5A,-5B, -6, -7A, -7B, -8, -8B, -9 and -10. At least four members of thisfamily are present in Drosophila; one of them, wingless (wg), isimplicated in segmentation polarity. All these proteins share thefollowing features characteristics of secretory proteins: a signalpeptide, several potential N-glycosylation sites and 22 conservedcysteines that are probably involved in disulfide bonds. The Wntproteins seem to adhere to the plasma membrane of the secreting cellsand are therefore likely to signal over only few cell diameters. Theconsensus pattern, which is based upon a highly conserved regionincluding three cysteines, is as follows: C-K-C-H-G-[LIVMT]-S-G-x-C. Allsequences known to belong to this family are detected by the providedconsensus pattern.

s) Ww/rsp5/WWP Domain-Containing Proteins. SEQ ID NOS:188, 379, and 395represent polynucleotides encoding a polypeptide in the family ofWW/rsp5/WWP domain-containing proteins. The WW domain (Bork et al.,Trends Biochem. Sci. (1994) 19:531; Andre et al., Biochem. Biophys. Res.Commun. (1994) 205:1201; Hofmann et al., FEBS Lett. (1995) 358:153; andSudol et al., FEBS Lett. (1995) 369:67), also known as rsp5 or WWP), wasoriginally discovered as a short conserved region in a number ofunrelated proteins, among them dystrophin, the gene responsible forDuchenne muscular dystrophy. The domain, which spans about 35 residues,is repeated up to 4 times in some proteins. It has been shown (Chen etal., Proc. Natl. Acad. Sci. USA (1995) 92:7819) to bind proteins withparticular proline-motifs, [AP]-P-P-[AP]-Y, and thus resembles somewhatSH3 domains. It appears to contain beta-strands grouped around fourconserved aromatic positions, generally Trp. The name WW or WWP derivesfrom the presence of these Trp as well as that of a conserved Pro. It isfrequently associated with other domains typical for proteins in signaltransduction processes.

Proteins containing the WW domain include:

1. Dystrophin, a multidomain cytoskeletal protein. Its longestalternatively spliced form consists of an N-terminal actin-bindingdomain, followed by 24 spectrin-like repeats, a cysteine-richcalcium-binding domain and a C-terminal globular domain. Dystrophinsform tetramers and is thought to have multiple functions includinginvolvement in membrane stability, transduction of contractile forces tothe extracellular environment and organization of membranespecialization. Mutations in the dystrophin gene lead to musculardystrophy of Duchenne or Becker type. Dystrophin contains one WW domainC-terminal of the spectrin-repeats.

2. Vertebrate YAP protein, which is a substrate of an unknown serinekinase. It binds to the SH3 domain of the Yes oncoprotein via aproline-rich region. This protein appears in alternatively splicedisoforms, containing either one or two WW domains.

3. IQGAP, which is a human GTPase activating protein acting on ras. Itcontains an N-terminal domain similar to fly muscle mp20 protein and aC-terminal ras GTPase activator domain.

For the sensitive detection of WW domains, the profile spans the wholehomology region as well as a pattern.

t) Zinc Finger, C2H2 Type. SEQ ID NO:61, 306, and 386 correspond topolynucleotides encoding novel members of the of the C2H2 type zincfinger protein family. Zinc finger domains (Klug et al., Trends Biochem.Sci. (1987) 12:464; Evans et al., Cell (1988) 52:1; Payre et al., FEBSLett. (1988) 234:245; Miller et al, EMBO J. (1985) 4:1609; and Berg,Proc. Natl. Acad. Sci. USA (1988) 85:99) are nucleic acid-bindingprotein structures first identified in the Xenopus transcription factorTFIIIA. These domains have since been found in numerous nucleicacid-binding proteins. A zinc finger domain is composed of 25 to 30amino acid residues. Two cysteine or histidine residues are positionedat both extremities of the domain, which are involved in the tetrahedralcoordination of a zinc atom. It has been proposed that such a domaininteracts with about five nucleotides.

Many classes of zinc fingers are characterized according to the numberand positions of the histidine and cysteine residues involved in thezinc atom coordination. In the first class to be characterized, calledC2H2, the first pair of zinc coordinating residues are cysteines, whilethe second pair are histidines. A number of experimental reports havedemonstrated the zinc-dependent DNA or RNA binding property of somemembers of this class.

Mammalian proteins having a C2H2 zipper include (number in parenthesisindicates number of zinc finger regions in the protein): basonuclin (6),BCL-6/LAZ-3 (6), erythroid krueppel-like transcription factor (3),transcription factors Sp1 (3), Sp2 (3), Sp3 (3) and Sp(4) 3,transcriptional repressor YY1 (4), Wilms' tumor protein (4), EGR1/Krox24(3), EGR2/Krox20 (3), EGR3/Pilot (3), EGR4/AT133 (4), Evi-1 (10), GLI1(5), GLI2 (4+), GLI3 (3+), HIV-EP1/ZNF40 (4), HIV-EP2 (2), KR1 (9+), KR2(9), KR3 (15+), KR4 (14+), KR5 (11+), HF.12 (6+), REX-1 (4), ZfX (13),ZfY (13), Zfp-35 (18), ZNF7 (15), ZNF8 (7), ZNF35 (10), ZNF42/MZF-1(13), ZNF43 (22), ZNF46/Kup (2), ZNF76 (7), ZNF91 (36), ZNF133 (3).

In addition to the conserved zinc ligand residues, it has been shownthat a number of other positions are also important for the structuralintegrity of the C2H2 zinc fingers. (Rosenfeld et al., J. Biomol.Struct. Dyn. (1993) 11:557) The best conserved position is found fourresidues after the second cysteine; it is generally an aromatic oraliphatic residue. The consensus pattern for C2H2 zinc fingers is:C-x(2,4)-C-x(3)-[LIVMFYWC]-x(8)-H-x(3,5)-H. The two C's and two H's arezinc ligands.

u) Zinc Finger, CCHC Class. SEQ ID NO:322 corresponds to apolynucleotide encoding a novel member of the zinc finger CCHC family.The CCHC zinc finger protein family to date has been mostly composed ofretroviral gag proteins (nucleocapsid). The prototype structure of thisfamily is from HIV. The family also contains members involved ineukaryotic gene regulation, such as C. elegans GLH-1. The consensussequence of this family is based upon the common structure of an18-residue zinc finger.

v) Zinc-Binding Metalloprotease Domain. SEQ ID NO:306 and 395 representpolynucleotides encoding novel members of the zinc-bindingmetalloprotease domain protein family. The majority of zinc-dependentmetallopeptidases (with the notable exception of the carboxypeptidases)share a common pattern of primary structure (Jongeneel et al., FEBSLett. (1989) 242:211; Murphy et al., FEBS Lett. (1991) 289:4; and Bodeet al., Zoology (1996) 99:237) in the part of their sequence involved inthe binding of zinc, and can be grouped together as a superfamily, knownas the metzincins, on the basis of this sequence similarity. Examples ofthese proteins include: 1) Angiotensin-converting enzyme (EC 3.4.15.1)(dipeptidyl carboxypeptidase I) (ACE), the enzyme responsible forhydrolyzing angiotensin I to angiotensin II. 2) Mammalian extracellularmatrix metalloproteinases (known as matrixins) (Woessner, FASEB J.(1991) 5:2145): MMP-1 (EC 3.4.24.7) (interstitial collagenase), MMP-2(EC 3.4.24.24) (72 Kd gelatinase), MMP-9 (EC 3.4.24.35) (92 Kdgelatinase), MMP-7 (EC 3.4.24.23) (matrylisin), MMP-8 (EC 3.4.24.34)(neutrophil collagenase), MMP-3 (EC 3.4.24.17) (stromelysin-1), MMP-10(EC 3.4.24.22) (stromelysin-2), and MMP-11 (stromelysin-3), MMP-12 (EC3.4.24.65) (macrophage metalloelastase). 3) Endothelin-converting enzyme1 (EC 3.4.24.71) (ECE-1), which processes the precursor of endothelin torelease the active peptide.

Example 4 Differential Expression of Polynucleotides of the Invention:Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the inventionwas assessed in several libraries prepared from various sources,including cell lines and patient tissue samples. Table 4 provides asummary of these libraries, including the shortened library name (usedhereafter), the mRNA source used to prepared the cDNA library, the“nickname” of the library that is used in the tables below (in quotes),and the approximate number of clones in the library. TABLE 4 Descriptionof cDNA Libraries Number of Clones Library in this (lib #) DescriptionClustering 1 Km12 L4 307133 Human Colon Cell Line, High MetastaticPotential (derived from Km12C) “High Colon” 2 Km12C 284755 Human ColonCell Line, Low Metastatic Potential “Low Colon” 3 MDA-MB-231 326937Human Breast Cancer Cell Line, High Metastatic Potential;micro-metastases in lung “High Breast” 4 MCF7 318979 Human Breast CancerCell, Non Metastatic “Low Breast” 8 MV-522 223620 Human Lung Cancer CellLine, High Metastatic Potential “High Lung” 9 UCP-3 312503 Human LungCancer Cell Line, Low Metastatic Potential “Low Lung” 12 Humanmicrovascular endothelial cells (HMEC) - 41938 Untreated PCR (OligodT)cDNA library 13 Human microvascular endothelial cells (HMEC) - 42100bFGF treated PCR (OligodT) cDNA library 14 Human microvascularendothelial cells (HMEC) - 42825 VEGF treated PCR (OligodT) cDNA library15 Normal Colon - UC#2 Patient 34285 PCR (OligodT) cDNA library “NormalColon Tumor Tissue” 16 Colon Tumor - UC#2 Patient 35625 PCR (OligodT)cDNA library “Normal Colon Tumor Tissue” 17 Liver Metastasis from ColonTumor of UC#2 36984 Patient PCR (OligodT) cDNA library “High ColonMetastasis Tissue” 18 Normal Colon - UC#3 Patient 36216 PCR (OligodT)cDNA library “Normal Colon Tumor Tissue” 19 Colon Tumor - UC#3 Patient41388 PCR (OligodT) cDNA library “High Colon Tumor Tissue” 20 LiverMetastasis from Colon Tumor of UC#3 30956 Patient PCR (OligodT) cDNAlibrary “High Colon Metastasis Tissue”

The KM12L4 and KM12C cell lines are described in Example 1 above. TheMDA-MB-231 cell line was originally isolated from pleural effusions(Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastaticpotential, and forms poorly differentiated adenocarcinoma grade II innude mice consistent with breast carcinoma. The MCF7 cell line wasderived from a pleural effusion of a breast adenocarcinoma and isnon-metastatic. The MV-522 cell line is derived from a human lungcarcinoma and is of high metastatic potential. The UCP-3 cell line is alow metastatic human lung carcinoma cell line; the MV-522 is a highmetastatic variant of UCP-3. These cell lines are well-recognized in theart as models for the study of human breast and lung cancer (see, e.g.,Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7);Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ransonet al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al.,Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al.,Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990)11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637;(MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); andZhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples oflibraries 15-20 are derived from two different patients (UC#2, andUC#3).

Each of the libraries is composed of a collection of cDNA clones that inturn are representative of the mRNAs expressed in the indicated mRNAsource. In order to facilitate the analysis of the millions of sequencesin each library, the sequences were assigned to clusters. The concept of“cluster of clones” is derived from a sorting/grouping of cDNA clonesbased on their hybridization pattern to a panel of roughly 300 7 bpoligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29).Random cDNA clones from a tissue library are hybridized at moderatestringency to 300 7 bp oligonucleotides. Each oligonucleotide has somemeasure of specific hybridization to that specific clone. Thecombination of 300 of these measures of hybridization for 300 probesequals the “hybridization signature” for a specific clone. Clones withsimilar sequence will have similar hybridization signatures. Bydeveloping a sorting/grouping algorithm to analyze these signatures,groups of clones in a library can be identified and brought togethercomputationally. These groups of clones are termed “clusters”. Dependingon the stringency of the selection in the algorithm (similar to thestringency of hybridization in a classic library cDNA screeningprotocol), the “purity” of each cluster can be controlled. For example,artifacts of clustering may occur in computational clustering just asartifacts can occur in “wet-lab” screening of a cDNA library with 400 bpcDNA fragments, at even the highest stringency. The stringency used inthe implementation of cluster herein provides groups of clones that arein general from the same cDNA or closely related cDNAs. Closely relatedclones can be a result of different length clones of the same cDNA,closely related clones from highly related gene families, or splicevariants of the same cDNA.

Differential expression for a selected cluster was assessed by firstdetermining the number of cDNA clones corresponding to the selectedcluster in the first library (Clones in 1^(st)), and the determining thenumber of cDNA clones corresponding to the selected cluster in thesecond library (Clones in 2^(nd)). Differential expression of theselected cluster in the first library relative to the second library isexpressed as a “ratio” of percent expression between the two libraries.In general, the “ratio” is calculated by: 1) calculating the percentexpression of the selected cluster in the first library by dividing thenumber of clones corresponding to a selected cluster in the firstlibrary by the total number of clones analyzed from the first library;2) calculating the percent expression of the selected cluster in thesecond library by dividing the number of clones corresponding to aselected cluster in a second library by the total number of clonesanalyzed from the second library; 3) dividing the calculated percentexpression from the first library by the calculated percent expressionfrom the second library. If the “number of clones” corresponding to aselected cluster in a library is zero, the value is set at 1 to aid incalculation. The formula used in calculating the ratio takes intoaccount the “depth” of each of the libraries being compared, i.e., thetotal number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentiallyexpressed between two samples when the ratio value is greater than atleast about 2, preferably greater than at least about 3, more preferablygreater than at least about 5, where the ratio value is calculated usingthe method described above. The significance of differential expressionis determined using a z score test (Zar, Biostatistical Analysis,Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298(1974).

Tables 5 to 7 (inserted before the claims) show the number of clones ineach of the above libraries that were analyzed for differentialexpression. Examples of differentially expressed polynucleotides ofparticular interest are described in more detail below. TABLE 5 ClusterClones in Clones in Clones in Clones in Clones in Clones Clone Name IDLib1 Lib2 Lib3 Lib4 Lib8 in Lib9 M00001340B:A06 17062 3 0 0 0 0 0M00001340D:F10 11589 2 2 1 3 3 8 M00001341A:E12 4443 10 6 2 6 3 11M00001342B:E06 39805 2 0 0 0 1 0 M00001343C:F10 2790 7 15 13 14 6 0M00001343D:H07 23255 3 0 1 1 0 0 M00001345A:E01 6420 8 0 2 0 1 0M00001346A:F09 5007 4 8 3 6 2 6 M00001346D:E03 6806 5 2 1 2 0 3M00001346D:G06 5779 5 4 3 4 0 0 M00001346D:G06 5779 5 4 3 4 0 0M00001347A:B10 13576 5 0 0 0 12 11 M00001348B:B04 16927 4 0 0 2 0 0M00001348B:G06 16985 4 0 0 0 0 0 M00001349B:B08 3584 5 11 5 0 0 2M00001350A:H01 7187 5 3 1 0 1 0 M00001351B:A08 3162 10 14 1 6 6 5M00001351B:A08 3162 10 14 1 6 6 5 M00001352A:E02 16245 4 0 0 0 0 0M00001353A:G12 8078 4 3 1 0 1 0 M00001353D:D10 14929 4 0 0 1 23 16M00001355B:G10 14391 3 1 0 0 0 0 M00001357D:D11 4059 8 6 8 16 0 1M00001361A:A05 4141 5 2 10 16 4 27 M00001361D:F08 2379 26 13 4 2 2 3M00001362B:D10 5622 7 4 2 13 1 2 M00001362C:H11 945 9 21 2 1 0 0M00001365C:C10 40132 2 0 0 0 3 0 M00001370A:C09 6867 7 3 0 0 0 0M00001371C:E09 7172 3 5 1 2 0 1 M00001376B:G06 17732 1 3 5 0 1 4M00001378B:B02 39833 2 0 0 0 0 0 M00001379A:A05 1334 27 38 35 28 3 0M00001380D:B09 39886 2 0 0 0 0 0 M00001382C:A02 22979 2 1 0 0 0 0M00001383A:C03 39648 2 0 0 0 0 0 M00001383A:C03 39648 2 0 0 0 0 0M00001386C:B12 5178 5 5 4 2 5 2 M00001387A:C05 2464 5 19 25 16 1 0M00001387B:G03 7587 6 2 1 0 0 0 M00001388D:G05 5832 10 3 0 1 5 0M00001389A:C08 16269 3 0 0 0 1 1 M00001394A:F01 6583 2 7 3 2 0 0M00001395A:C03 4016 5 14 0 6 0 0 M00001396A:C03 4009 6 4 13 5 4 10M00001402A:E08 39563 2 0 0 0 0 0 M00001407B:D11 5556 8 1 5 0 2 0M00001409C:D12 9577 5 2 0 1 11 12 M00001410A:D07 7005 8 2 0 0 0 0M00001412B:B10 8551 4 4 0 3 0 0 M00001415A:H06 13538 5 0 0 0 9 1M00001416A:H01 7674 5 2 0 5 0 0 M00001416B:H11 8847 4 1 3 0 6 1M00001417A:E02 36393 2 0 0 1 0 0 M00001418B:F03 9952 4 2 1 1 0 0M00001418D:B06 8526 3 2 1 5 1 0 M00001421C:F01 9577 5 2 0 1 11 12M00001423B:E07 15066 4 0 0 0 0 0 M00001424B:G09 10470 5 1 0 2 0 1M00001425B:H08 22195 3 0 0 0 0 0 M00001426D:C08 4261 4 9 7 9 12 15M00001428A:H10 84182 1 0 0 0 0 0 M00001429A:H04 2797 15 11 18 16 1 14M00001429B:A11 4635 7 9 2 0 0 0 M00001429D:D07 40392 2 0 1 8 12 16M00001439C:F08 40054 1 0 0 0 0 0 M00001442C:D07 16731 3 1 0 0 0 0M00001445A:F05 13532 3 2 1 0 1 2 M00001446A:F05 7801 5 2 4 6 1 0M00001447A:G03 10717 7 2 0 5 8 0 M00001448D:C09 8 1850 2127 1703 31331355 122 M00001448D:H01 36313 2 0 0 0 1 30 M00001449A:A12 5857 6 2 3 4 00 M00001449A:B12 41633 1 1 0 0 0 0 M00001449A:D12 3681 12 5 10 1 2 5M00001449A:G10 36535 2 0 0 0 0 0 M00001449C:D06 86110 1 0 0 0 0 0M00001450A:A02 39304 2 0 0 0 0 0 M00001450A:A11 32663 1 1 0 0 0 0M00001450A:B12 82498 1 0 0 0 0 0 M00001450A:D08 27250 2 0 0 0 0 0M00001452A:B04 84328 1 0 0 0 0 0 M00001452A:B12 86859 1 0 0 0 0 0M00001452A:D08 1120 44 41 5 11 5 0 M00001452A:F05 85064 1 0 0 0 0 0M00001452C:B06 16970 4 0 0 0 3 4 M00001453A:E11 16130 3 1 0 0 0 1M00001453C:F06 16653 3 1 0 0 0 0 M00001454A:A09 83103 1 0 0 0 0 0M00001454B:C12 7005 8 2 0 0 0 0 M00001454D:G03 689 58 95 17 36 66 95M00001455A:E09 13238 4 1 0 0 0 0 M00001455B:E12 13072 4 1 0 0 0 0M00001455D:F09 9283 4 1 0 1 0 1 M00001455D:F09 9283 4 1 0 1 0 1M00001460A:F06 2448 23 22 2 3 3 1 M00001460A:F12 39498 2 0 0 0 0 0M00001461A:D06 1531 20 23 32 17 14 14 M00001463C:B11 19 1415 1203 1364525 479 774 M00001465A:B11 10145 2 0 2 0 0 0 M00001466A:E07 4275 11 2 50 4 2 M00001467A:B07 38759 2 0 0 0 1 1 M00001467A:D04 39508 2 0 0 0 0 0M00001467A:D08 16283 3 0 0 0 0 0 M00001467A:D08 16283 3 0 0 0 0 0M00001467A:E10 39442 2 0 0 0 0 0 M00001468A:F05 7589 6 2 1 1 1 0M00001469A:C10 12081 4 0 0 0 0 0 M00001469A:H12 19105 2 0 2 0 1 0M00001470A:B10 1037 53 48 4 22 0 0 M00001470A:C04 39425 2 0 0 0 0 0M00001471A:B01 39478 2 0 0 0 0 0 M00001481D:A05 7985 3 1 4 0 1 0M00001490B:C04 18699 2 1 0 0 0 3 M00001494D:F06 7206 4 3 3 1 2 0M00001497A:G02 2623 12 4 31 4 6 1 M00001499B:A11 10539 2 1 1 0 1 0M00001500A:C05 5336 9 2 4 8 3 15 M00001500A:E11 2623 12 4 31 4 6 1M00001500C:E04 9443 4 2 1 1 0 0 M00001501D:C02 9685 3 2 0 7 2 3M00001504C:A07 10185 5 1 0 0 2 4 M00001504C:H06 6974 7 3 0 1 0 0M00001504D:G06 6420 8 0 2 0 1 0 M00001507A:H05 39168 2 0 0 0 0 0M00001511A:H06 39412 2 0 0 0 0 0 M00001512A:A09 39186 2 0 0 0 0 0M00001512D:G09 3956 9 9 5 2 0 0 M00001513A:B06 4568 10 4 0 9 2 0M00001513C:E08 14364 1 0 0 0 0 0 M00001514C:D11 40044 2 0 0 0 0 0M00001517A:B07 4313 13 6 1 0 1 0 M00001518C:B11 8952 3 4 0 4 2 0M00001528A:C04 7337 4 4 3 16 12 21 M00001528A:F09 18957 3 0 0 0 0 0M00001528B:H04 8358 3 3 2 0 0 0 M00001531A:D01 38085 2 0 0 0 0 0M00001532B:A06 3990 6 12 4 1 3 1 M00001533A:C11 2428 14 14 13 9 2 19M00001534A:C04 16921 4 0 0 1 2 1 M00001534A:D09 5097 6 5 1 1 3 2M00001534A:F09 5321 11 7 1 5 10 26 M00001534C:A01 4119 9 4 2 2 5 3M00001535A:B01 7665 3 1 5 0 0 0 M00001535A:C06 20212 2 0 1 1 0 0M00001535A:F10 39423 2 0 0 0 0 0 M00001536A:B07 2696 23 11 9 18 10 21M00001536A:C08 39392 2 0 0 0 0 0 M00001537A:F12 39420 2 0 0 0 0 0M00001537B:G07 3389 4 11 13 2 0 0 M00001540A:D06 8286 6 1 0 3 4 0M00001541A:D02 3765 19 6 0 0 0 0 M00001541A:F07 22085 3 0 0 0 0 1M00001541A:H03 39174 2 0 0 0 0 0 M00001542A:A09 22113 3 0 0 0 0 0M00001542A:E06 39453 2 0 0 0 0 0 M00001544A:E03 12170 2 1 2 0 0 0M00001544A:G02 19829 2 0 1 0 0 0 M00001544B:B07 6974 7 3 0 1 0 0M00001545A:C03 19255 2 0 0 0 0 0 M00001545A:D08 13864 3 0 2 1 2 4M00001546A:G11 1267 43 55 5 0 0 0 M00001548A:E10 5892 5 1 4 4 1 3M00001548A:H09 1058 40 44 37 47 39 59 M00001549A:B02 4015 10 5 8 15 2 0M00001549A:D08 10944 3 0 3 1 0 7 M00001549B:F06 4193 12 7 2 2 0 1M00001549C:E06 16347 4 0 0 0 0 0 M00001550A:A03 7239 5 2 1 0 2 0M00001550A:G01 5175 8 1 3 2 0 0 M00001551A:B10 6268 6 4 3 18 5 0M00001551A:F05 39180 2 0 0 0 0 0 M00001551A:G06 22390 2 1 0 0 0 1M00001551C:G09 3266 12 14 0 1 0 6 M00001552A:B12 307 73 60 196 75 79 27M00001552A:D11 39458 2 0 0 0 0 0 M00001552B:D04 5708 5 4 4 3 1 4M00001553A:H06 8298 4 3 1 3 0 0 M00001553B:F12 4573 5 7 2 5 0 1M00001553D:D10 22814 3 0 0 0 0 0 M00001555A:B02 39539 2 0 0 0 1 0M00001555A:C01 39195 2 0 0 0 0 0 M00001555D:G10 4561 8 4 4 8 0 0M00001556A:C09 9244 2 0 3 2 10 17 M00001556A:F11 1577 12 40 25 3 4 0M00001556A:H01 15855 2 1 1 2 12 213 M00001556B:C08 4386 7 8 3 1 3 21M00001556B:G02 11294 4 0 2 0 0 1 M00001557A:D02 7065 5 3 2 1 0 0M00001557A:D02 7065 5 3 2 1 0 0 M00001557A:F01 9635 3 0 2 1 0 0M00001557A:F03 39490 2 0 0 0 1 0 M00001557B:H10 5192 8 5 0 5 0 0M00001557D:D09 8761 3 4 0 1 0 1 M00001558B:H11 7514 5 3 0 0 0 0M00001560D:F10 6558 4 3 4 0 0 5 M00001561A:C05 39486 2 0 0 0 0 0M00001563B:F06 102 289 233 278 116 123 184 M00001564A:B12 5053 11 4 2 21 1 M00001571C:H06 5749 4 1 9 0 0 0 M00001578B:E04 23001 2 1 0 2 0 0M00001579D:C03 6539 8 3 0 0 0 1 M00001583D:A10 6293 3 5 2 6 0 0M00001586C:C05 4623 3 4 12 2 1 1 M00001587A:B11 39380 2 0 0 0 0 0M00001594B:H04 260 189 188 27 2 15 0 M00001597C:H02 4837 6 2 10 0 3 1M00001597D:C05 10470 5 1 0 2 0 1 M00001598A:G03 16999 4 0 0 0 0 0M00001601A:D08 22794 2 0 0 0 0 0 M00001604A:B10 1399 49 27 19 7 10 23M00001604A:F05 39391 2 0 0 0 0 0 M00001607A:E11 11465 5 0 0 0 0 0M00001608A:B03 7802 5 4 0 1 0 0 M00001608B:E03 22155 3 0 0 0 0 0M00001614C:F10 13157 4 1 0 3 1 0 M00001617C:E02 17004 4 0 1 0 1 0M00001619C:F12 40314 2 0 0 0 1 0 M00001621C:C08 40044 2 0 0 0 0 0M00001623D:F10 13913 2 1 2 0 0 1 M00001624A:B06 3277 10 11 8 3 5 1M00001624C:F01 4309 4 13 3 10 0 0 M00001630B:H09 5214 10 2 2 2 4 3M00001644C:B07 39171 2 0 0 0 0 0 M00001645A:C12 19267 2 0 0 0 0 1M00001648C:A01 4665 5 9 0 0 0 0 M00001657D:C03 23201 3 0 0 0 3 0M00001657D:F08 76760 1 0 2 2 0 5 M00001662C:A09 23218 3 0 0 0 0 0M00001663A:E04 35702 2 0 0 0 0 0 M00001669B:F02 6468 4 3 3 8 1 0M00001670C:H02 14367 3 0 0 0 0 0 M00001673C:H02 7015 6 3 1 2 1 1M00001675A:C09 8773 4 1 4 4 4 6 M00001676B:F05 11460 4 2 0 0 0 0M00001677C:E10 14627 1 2 1 0 1 0 M00001677D:A07 7570 5 3 0 0 0 0M00001678D:F12 4416 9 5 2 6 1 3 M00001679A:A06 6660 7 0 4 2 1 0M00001679A:F10 26875 1 0 0 0 1 0 M00001679B:F01 6298 2 4 5 3 1 0M00001679C:F01 78091 1 0 0 0 0 0 M00001679D:D03 10751 3 2 0 1 0 1M00001679D:D03 10751 3 2 0 1 0 1 M00001680D:F08 10539 2 1 1 0 1 0M00001682C:B12 17055 4 0 0 0 0 0 M00001686A:E06 4622 7 6 4 2 3 0M00001688C:F09 5382 6 2 6 2 0 3 M00001693C:G01 4393 10 6 2 4 1 1M00001716D:H05 67252 1 0 0 1 0 0 M00003741D:C09 40108 2 0 0 0 0 0M00003747D:C05 11476 6 0 0 0 0 0 M00003759B:B09 697 76 52 30 72 21 30M00003762C:B08 17076 4 0 0 0 0 0 M00003763A:F06 3108 14 11 7 5 0 1M00003774C:A03 67907 1 0 0 0 0 0 M00003796C:D05 5619 3 5 3 3 0 4M00003826B:A06 11350 3 3 0 0 1 0 M00003833A:E05 21877 2 1 0 0 0 1M00003837D:A01 7899 5 4 0 2 1 0 M00003839A:D08 7798 5 2 2 0 0 1M00003844C:B11 6539 8 3 0 0 0 1 M00003846B:D06 6874 6 3 0 0 0 0M00003851B:D10 13595 4 0 1 0 0 1 M00003853A:D04 5619 3 5 3 3 0 4M00003853A:F12 10515 5 1 0 1 1 2 M00003856B:C02 4622 7 6 4 2 3 0M00003857A:G10 3389 4 11 13 2 0 0 M00003857A:H03 4718 4 5 5 2 4 6M00003871C:E02 4573 5 7 2 5 0 1 M00003875B:F04 12977 5 0 0 0 0 0M00003875B:F04 12977 5 0 0 0 0 0 M00003875C:G07 8479 4 3 1 1 2 4M00003876D:E12 7798 5 2 2 0 0 1 M00003879B:C11 5345 7 1 7 4 6 27M00003879B:D10 31587 1 1 0 0 1 0 M00003879D:A02 14507 3 1 0 0 3 1M00003885C:A02 13576 5 0 0 0 12 11 M00003885C:A02 13576 5 0 0 0 12 11M00003906C:E10 9285 4 3 0 0 1 2 M00003907D:A09 39809 1 0 0 0 2 1M00003907D:H04 16317 3 0 0 0 0 0 M00003909D:C03 8672 4 4 0 0 0 0M00003912B:D01 12532 4 1 0 1 0 1 M00003914C:F05 3900 9 6 8 1 7 13M00003922A:E06 23255 3 0 1 1 0 0 M00003958A:H02 18957 3 0 0 0 0 0M00003958A:H02 18957 3 0 0 0 0 0 M00003958C:G10 40455 2 0 0 0 0 0M00003958C:G10 40455 2 0 0 0 0 0 M00003968B:F06 24488 2 0 1 4 0 0M00003970C:B09 40122 2 0 0 0 0 0 M00003974D:E07 23210 3 0 0 0 0 0M00003974D:H02 23358 3 0 0 0 1 0 M00003975A:G11 12439 4 0 0 0 0 0M00003978B:G05 5693 7 4 1 3 1 1 M00003981A:E10 3430 9 10 7 3 0 0M00003982C:C02 2433 10 13 21 18 8 8 M00003983A:A05 9105 5 1 1 1 0 0M00004028D:A06 6124 4 8 1 9 1 0 M00004028D:C05 40073 2 0 1 0 0 1M00004031A:A12 9061 5 2 0 0 0 0 M00004031A:A12 9061 5 2 0 0 0 0M00004035C:A07 37285 2 0 0 1 0 1 M00004035D:B06 17036 4 0 0 0 0 0M00004059A:D06 5417 10 4 0 9 2 0 M00004068B:A01 3706 7 14 4 22 1 0M00004072B:B05 17036 4 0 0 0 0 0 M00004081C:D10 15069 3 0 0 1 0 0M00004081C:D12 14391 3 1 0 0 0 0 M00004086D:G06 9285 4 3 0 0 1 2M00004087D:A01 6880 2 6 1 1 0 0 M00004093D:B12 5325 5 5 2 0 2 1M00004093D:B12 5325 5 5 2 0 2 1 M00004105C:A04 7221 5 2 2 2 0 0M00004108A:E06 4937 4 9 3 1 3 1 M00004111D:A08 6874 6 3 0 0 0 0M00004114C:F11 13183 2 3 0 7 0 1 M00004138B:H02 13272 3 2 0 3 0 0M00004146C:C11 5257 2 8 5 5 5 25 M00004151D:B08 16977 4 0 0 0 0 0M00004157C:A09 6455 3 1 6 0 0 0 M00004169C:C12 5319 6 2 8 2 2 3M00004171D:B03 4908 6 7 2 2 2 0 M00004172C:D08 11494 4 0 0 0 0 0M00004183C:D07 16392 3 0 0 0 0 0 M00004185C:C03 11443 5 1 0 0 0 0M00004197D:H01 8210 2 6 0 0 0 0 M00004203B:C12 14311 4 0 0 0 1 2M00004212B:C07 2379 26 13 4 2 2 3 M00004214C:H05 11451 3 2 1 2 1 1M00004223A:G10 16918 4 0 0 0 0 0 M00004223B:D09 7899 5 4 0 2 1 0M00004223D:E04 12971 4 0 0 0 1 0 M00004229B:F08 6455 3 1 6 0 0 0M00004230B:C07 7212 3 5 2 1 3 0 M00004269D:D06 4905 7 6 3 1 3 1M00004275C:C11 16914 3 0 0 1 0 0 M00004283B:A04 14286 3 1 0 1 1 1M00004285B:E08 56020 1 0 0 0 0 0 M00004295D:F12 16921 4 0 0 1 2 1M00004296C:H07 13046 4 1 0 1 0 0 M00004307C:A06 9457 2 0 5 0 3 0M00004312A:G03 26295 2 0 0 0 0 0 M00004318C:D10 21847 2 1 0 0 0 0M00004372A:A03 2030 13 10 32 4 0 0 M00004377C:F05 2102 12 20 23 21 6 5

TABLE 6 Clones in Clones in Clones in Clones in Clones in Clones inClone Name Cluster ID Lib15 Lib16b Lib17 Lib18 Lib19 Lib20M00001340B:A06 17062 0 0 0 0 0 0 M00001340D:F10 11589 0 0 0 0 0 0M00001341A:E12 4443 0 0 0 1 0 0 M00001342B:E06 39805 0 0 0 0 0 0M00001343C:F10 2790 0 0 0 0 0 0 M00001343D:H07 23255 0 0 0 0 0 0M00001345A:E01 6420 0 0 0 0 0 0 M00001346A:F09 5007 0 0 0 0 0 0M00001346D:E03 6806 0 0 0 0 0 0 M00001346D:G06 5779 0 0 0 0 0 0M00001346D:G06 5779 0 0 0 0 0 0 M00001347A:B10 13576 0 0 0 0 0 0M00001348B:B04 16927 0 0 0 0 0 0 M00001348B:G06 16985 0 0 0 0 0 0M00001349B:B08 3584 0 0 0 0 0 0 M00001350A:H01 7187 0 0 0 0 0 0M00001351B:A08 3162 0 1 0 0 1 0 M00001351B:A08 3162 0 1 0 0 1 0M00001352A:E02 16245 0 0 0 0 0 0 M00001353A:G12 8078 0 0 0 0 0 0M00001353D:D10 14929 0 3 1 0 5 0 M00001355B:G10 14391 0 0 0 0 0 0M00001357D:D11 4059 0 0 0 0 0 0 M00001361A:A05 4141 0 0 0 0 0 0M00001361D:F08 2379 0 0 0 0 0 0 M00001362B:D10 5622 0 0 0 0 0 0M00001362C:H11 945 0 0 0 0 0 1 M00001365C:C10 40132 0 0 0 0 0 0M00001370A:C09 6867 0 0 0 0 0 0 M00001371C:E09 7172 0 0 0 0 0 0M00001376B:G06 17732 0 0 0 0 0 1 M00001378B:B02 39833 0 0 0 0 0 0M00001379A:A05 1334 0 0 0 0 0 1 M00001380D:B09 39886 0 0 0 0 0 0M00001382C:A02 22979 0 0 0 0 0 0 M00001383A:C03 39648 0 0 0 0 0 0M00001383A:C03 39648 0 0 0 0 0 0 M00001386C:B12 5178 0 0 0 0 0 0M00001387A:C05 2464 0 0 0 0 0 0 M00001387B:G03 7587 0 0 0 0 0 0M00001388D:G05 5832 0 0 0 0 0 0 M00001389A:C08 16269 0 1 0 0 0 0M00001394A:F01 6583 1 4 1 0 0 0 M00001395A:C03 4016 0 0 0 0 0 0M00001396A:C03 4009 0 0 0 0 0 0 M00001402A:E08 39563 0 0 0 0 0 0M00001407B:D11 5556 0 0 0 0 0 0 M00001409C:D12 9577 0 0 0 0 0 0M00001410A:D07 7005 0 0 0 0 0 0 M00001412B:B10 8551 0 0 0 0 0 0M00001415A:H06 13538 0 0 0 0 0 0 M00001416A:H01 7674 0 0 0 0 0 0M00001416B:H11 8847 0 0 0 0 0 0 M00001417A:E02 36393 0 0 0 0 0 0M00001418B:F03 9952 0 0 0 0 0 0 M00001418D:B06 8526 0 0 0 0 0 0M00001421C:F01 9577 0 0 0 0 0 0 M00001423B:E07 15066 0 0 0 0 0 0M00001424B:G09 10470 0 0 0 0 0 0 M00001425B:H08 22195 0 0 0 0 0 0M00001426D:C08 4261 0 0 1 0 0 1 M00001428A:H10 84182 0 0 0 0 0 0M00001429A:H04 2797 0 0 0 0 0 0 M00001429B:A11 4635 0 0 0 0 0 0M00001429D:D07 40392 0 0 0 0 0 0 M00001439C:F08 40054 0 0 0 0 0 0M00001442C:D07 16731 0 0 0 0 0 0 M00001445A:F05 13532 0 0 0 0 0 0M00001446A:F05 7801 0 0 0 0 0 0 M00001447A:G03 10717 0 0 0 0 0 0M00001448D:C09 8 1 6 6 1 14 1 M00001448D:H01 36313 0 3 0 0 3 0M00001449A:A12 5857 0 0 0 0 0 0 M00001449A:B12 41633 0 0 0 0 0 0M00001449A:D12 3681 0 0 0 0 0 0 M00001449A:G10 36535 0 0 0 0 0 0M00001449C:D06 86110 0 0 0 0 0 0 M00001450A:A02 39304 0 0 0 0 0 0M00001450A:A11 32663 0 0 0 0 0 0 M00001450A:B12 82498 0 0 0 0 0 0M00001450A:D08 27250 0 0 0 0 0 0 M00001452A:B04 84328 0 0 0 0 0 0M00001452A:B12 86859 0 0 0 0 0 0 M00001452A:D08 1120 0 0 0 0 0 0M00001452A:F05 85064 0 0 0 0 0 0 M00001452C:B06 16970 0 0 2 0 1 0M00001453A:E11 16130 0 0 0 0 0 0 M00001453C:F06 16653 0 0 0 0 0 0M00001454A:A09 83103 0 0 0 0 0 0 M00001454B:C12 7005 0 0 0 0 0 0M00001454D:G03 689 0 2 2 0 4 2 M00001455A:E09 13238 0 0 0 0 0 0M00001455B:E12 13072 0 0 0 0 0 0 M00001455D:F09 9283 0 0 0 0 0 0M00001455D:F09 9283 0 0 0 0 0 0 M00001460A:F06 2448 0 0 0 0 0 0M00001460A:F12 39498 0 0 0 0 0 0 M00001461A:D06 1531 0 0 0 0 0 0M00001463C:B11 19 2 13 13 0 69 10 M00001465A:B11 10145 0 0 0 0 0 0M00001466A:E07 4275 0 0 0 0 0 0 M00001467A:B07 38759 0 0 0 0 0 0M00001467A:D04 39508 0 0 0 0 0 0 M00001467A:D08 16283 0 0 0 0 0 0M00001467A:D08 16283 0 0 0 0 0 0 M00001467A:E10 39442 0 0 0 0 0 0M00001468A:F05 7589 0 0 0 0 0 0 M00001469A:C10 12081 0 0 0 0 0 0M00001469A:H12 19105 0 0 0 0 0 0 M00001470A:B10 1037 0 0 0 0 0 0M00001470A:C04 39425 0 0 0 0 0 0 M00001471A:B01 39478 0 0 0 0 0 0M00001481D:A05 7985 0 0 0 0 0 0 M00001490B:C04 18699 0 0 0 0 0 0M00001494D:F06 7206 0 0 0 0 0 0 M00001497A:G02 2623 0 0 0 0 0 0M00001499B:A11 10539 0 0 0 0 0 0 M00001500A:C05 5336 0 0 0 0 0 0M00001500A:E11 2623 0 0 0 0 0 0 M00001500C:E04 9443 0 0 0 0 0 0M00001501D:C02 9685 0 0 0 0 0 0 M00001504C:A07 10185 0 0 0 0 0 0M00001504C:H06 6974 0 0 0 0 0 0 M00001504D:G06 6420 0 0 0 0 0 0M00001507A:H05 39168 0 0 0 0 0 0 M00001511A:H06 39412 0 0 0 0 0 0M00001512A:A09 39186 0 0 0 0 0 0 M00001512D:G09 3956 0 0 1 0 0 0M00001513A:B06 4568 0 0 0 0 0 0 M00001513C:E08 14364 0 0 0 0 0 0M00001514C:D11 40044 0 1 0 0 0 0 M00001517A:B07 4313 0 0 0 0 0 0M00001518C:B11 8952 0 0 0 0 0 0 M00001528A:C04 7337 0 0 0 0 0 0M00001528A:F09 18957 0 0 0 0 0 0 M00001528B:H04 8358 0 0 0 0 0 0M00001531A:D01 38085 0 0 0 0 0 0 M00001532B:A06 3990 1 1 0 0 0 0M00001533A:C11 2428 0 0 1 0 0 0 M00001534A:C04 16921 0 0 0 0 0 0M00001534A:D09 5097 0 0 0 0 0 0 M00001534A:F09 5321 0 1 0 0 2 0M00001534C:A01 4119 0 0 0 0 0 0 M00001535A:B01 7665 0 0 0 0 0 0M00001535A:C06 20212 0 0 0 0 0 0 M00001535A:F10 39423 0 0 0 0 0 0M00001536A:B07 2696 0 0 0 0 3 0 M00001536A:C08 39392 0 0 0 0 0 0M00001537A:F12 39420 0 0 0 0 0 0 M00001537B:G07 3389 0 0 0 0 0 0M00001540A:D06 8286 0 0 0 0 0 0 M00001541A:D02 3765 0 0 0 0 0 0M00001541A:F07 22085 0 0 0 0 0 0 M00001541A:H03 39174 0 0 0 0 0 0M00001542A:A09 22113 0 0 0 0 0 0 M00001542A:E06 39453 0 0 0 0 0 0M00001544A:E03 12170 0 0 0 0 0 0 M00001544A:G02 19829 0 0 0 0 0 0M00001544B:B07 6974 0 0 0 0 0 0 M00001545A:C03 19255 0 0 0 0 0 0M00001545A:D08 13864 0 0 0 0 0 0 M00001546A:G11 1267 1 0 0 0 7 0M00001548A:E10 5892 0 0 0 0 0 0 M00001548A:H09 1058 0 0 1 0 0 0M00001549A:B02 4015 0 0 0 0 0 0 M00001549A:D08 10944 0 0 0 0 0 0M00001549B:F06 4193 0 0 0 0 0 0 M00001549C:E06 16347 0 0 0 0 0 0M00001550A:A03 7239 0 0 0 0 0 0 M00001550A:G01 5175 0 0 0 0 0 0M00001551A:B10 6268 0 0 0 0 0 0 M00001551A:F05 39180 0 0 0 0 0 0M00001551A:G06 22390 0 0 0 0 0 0 M00001551C:G09 3266 0 0 1 0 0 0M00001552A:B12 307 0 0 0 0 3 0 M00001552A:D11 39458 0 0 0 0 0 0M00001552B:D04 5708 0 1 0 0 0 0 M00001553A:H06 8298 0 0 0 0 0 0M00001553B:F12 4573 0 0 0 0 0 0 M00001553D:D10 22814 0 0 0 0 0 0M00001555A:B02 39539 0 0 0 0 0 0 M00001555A:C01 39195 0 0 0 0 0 0M00001555D:G10 4561 0 0 0 0 0 0 M00001556A:C09 9244 0 0 0 0 0 0M00001556A:F11 1577 0 0 0 0 0 0 M00001556A:H01 15855 3 5 5 0 3 1M00001556B:C08 4386 1 2 0 0 0 0 M00001556B:G02 11294 0 0 0 0 0 0M00001557A:D02 7065 0 0 0 0 0 0 M00001557A:D02 7065 0 0 0 0 0 0M00001557A:F01 9635 0 0 0 0 0 0 M00001557A:F03 39490 0 0 0 0 0 0M00001557B:H10 5192 0 0 0 0 0 0 M00001557D:D09 8761 0 0 0 0 0 0M00001558B:H11 7514 0 0 0 0 0 0 M00001560D:F10 6558 0 0 0 0 0 0M00001561A:C05 39486 0 0 0 0 0 0 M00001563B:F06 102 22 38 65 7 43 10M00001564A:B12 5053 0 0 1 0 0 0 M00001571C:H06 5749 0 0 0 0 0 0M00001578B:E04 23001 0 0 0 0 0 0 M00001579D:C03 6539 0 0 0 0 0 0M00001583D:A10 6293 0 0 0 0 0 0 M00001586C:C05 4623 0 0 0 0 1 0M00001587A:B11 39380 0 0 0 0 0 0 M00001594B:H04 260 0 0 0 0 1 0M00001597C:H02 4837 0 0 0 0 0 0 M00001597D:C05 10470 0 0 0 0 0 0M00001598A:G03 16999 1 1 1 0 0 0 M00001601A:D08 22794 0 0 0 0 0 0M00001604A:B10 1399 0 0 0 0 0 0 M00001604A:F05 39391 0 0 0 0 0 0M00001607A:E11 11465 0 0 0 0 0 0 M00001608A:B03 7802 0 0 0 0 0 0M00001608B:E03 22155 0 0 0 0 0 0 M00001614C:F10 13157 0 0 0 0 0 0M00001617C:E02 17004 0 0 0 0 1 0 M00001619C:F12 40314 0 0 0 0 0 0M00001621C:C08 40044 0 1 0 0 0 0 M00001623D:F10 13913 0 0 0 0 0 0M00001624A:B06 3277 0 0 0 0 0 0 M00001624C:F01 4309 0 0 0 0 0 0M00001630B:H09 5214 1 0 0 1 1 0 M00001644C:B07 39171 0 0 0 0 0 0M00001645A:C12 19267 0 0 0 0 1 0 M00001648C:A01 4665 0 0 0 0 0 0M00001657D:C03 23201 0 0 0 0 0 0 M00001657D:F08 76760 0 0 0 0 0 0M00001662C:A09 23218 0 0 0 0 0 0 M00001663A:E04 35702 0 0 0 0 0 0M00001669B:F02 6468 0 0 0 0 0 0 M00001670C:H02 14367 0 0 0 0 0 0M00001673C:H02 7015 0 0 0 0 0 0 M00001675A:C09 8773 0 0 0 0 0 0M00001676B:F05 11460 0 0 0 0 0 0 M00001677C:E10 14627 0 1 0 0 0 0M00001677D:A07 7570 0 0 0 0 0 0 M00001678D:F12 4416 0 0 0 0 0 0M00001679A:A06 6660 0 0 0 0 0 0 M00001679A:F10 26875 0 0 0 0 0 0M00001679B:F01 6298 0 0 0 0 0 0 M00001679C:F01 78091 0 0 0 0 0 0M00001679D:D03 10751 0 0 0 0 0 0 M00001679D:D03 10751 0 0 0 0 0 0M00001680D:F08 10539 0 0 0 0 0 0 M00001682C:B12 17055 0 0 0 0 0 0M00001686A:E06 4622 0 0 0 0 0 0 M00001688C:F09 5382 0 0 0 0 0 0M00001693C:G01 4393 0 0 0 0 0 0 M00001716D:H05 67252 0 0 0 0 0 0M00003741D:C09 40108 0 0 0 0 0 0 M00003747D:C05 11476 0 0 0 0 0 0M00003759B:B09 697 0 0 0 0 1 0 M00003762C:B08 17076 0 0 0 0 0 0M00003763A:F06 3108 0 0 0 0 0 0 M00003774C:A03 67907 0 0 0 0 0 0M00003796C:D05 5619 0 0 0 0 0 0 M00003826B:A06 11350 0 0 0 0 0 0M00003833A:E05 21877 0 0 0 0 0 0 M00003837D:A01 7899 0 0 0 0 0 0M00003839A:D08 7798 0 0 0 0 0 0 M00003844C:B11 6539 0 0 0 0 0 0M00003846B:D06 6874 0 0 1 0 0 0 M00003851B:D10 13595 0 0 0 0 0 0M00003853A:D04 5619 0 0 0 0 0 0 M00003853A:F12 10515 0 0 0 0 0 0M00003856B:C02 4622 0 0 0 0 0 0 M00003857A:G10 3389 0 0 0 0 0 0M00003857A:H03 4718 0 0 0 0 0 0 M00003871C:E02 4573 0 0 0 0 0 0M00003875B:F04 12977 0 0 0 0 0 0 M00003875B:F04 12977 0 0 0 0 0 0M00003875C:G07 8479 0 0 0 0 0 1 M00003876D:E12 7798 0 0 0 0 0 0M00003879B:C11 5345 0 0 0 2 0 1 M00003879B:D10 31587 0 0 0 0 0 0M00003879D:A02 14507 0 0 0 0 0 0 M00003885C:A02 13576 0 0 0 0 0 0M00003885C:A02 13576 0 0 0 0 0 0 M00003906C:E10 9285 0 0 0 0 0 0M00003907D:A09 39809 0 0 0 0 0 0 M00003907D:H04 16317 0 0 0 0 0 0M00003909D:C03 8672 0 0 0 0 0 0 M00003912B:D01 12532 0 0 0 0 0 0M00003914C:F05 3900 0 0 0 0 1 0 M00003922A:E06 23255 0 0 0 0 0 0M00003958A:H02 18957 0 0 0 0 0 0 M00003958A:H02 18957 0 0 0 0 0 0M00003958C:G10 40455 0 0 0 0 0 0 M00003958C:G10 40455 0 0 0 0 0 0M00003968B:F06 24488 0 0 0 0 0 0 M00003970C:B09 40122 0 0 0 0 0 0M00003974D:E07 23210 0 0 0 0 0 0 M00003974D:H02 23358 0 0 0 0 0 0M00003975A:G11 12439 0 0 0 0 0 0 M00003978B:G05 5693 0 0 0 0 0 0M00003981A:E10 3430 0 0 0 0 1 0 M00003982C:C02 2433 0 0 0 0 0 0M00003983A:A05 9105 0 0 0 0 0 0 M00004028D:A06 6124 0 0 0 0 0 0M00004028D:C05 40073 0 0 0 0 0 0 M00004031A:A12 9061 0 0 0 0 0 0M00004031A:A12 9061 0 0 0 0 0 0 M00004035C:A07 37285 0 0 0 0 0 0M00004035D:B06 17036 0 0 0 0 0 0 M00004059A:D06 5417 0 0 0 0 0 0M00004068B:A01 3706 0 0 0 0 0 0 M00004072B:B05 17036 0 0 0 0 0 0M00004081C:D10 15069 0 0 0 0 0 0 M00004081C:D12 14391 0 0 0 0 0 0M00004086D:G06 9285 0 0 0 0 0 0 M00004087D:A01 6880 0 0 0 0 0 0M00004093D:B12 5325 1 1 0 1 0 1 M00004093D:B12 5325 1 1 0 1 0 1M00004105C:A04 7221 0 0 0 0 0 0 M00004108A:E06 4937 0 0 0 0 0 0M00004111D:A08 6874 0 0 1 0 0 0 M00004114C:F11 13183 0 0 0 0 0 0M00004138B:H02 13272 0 0 0 0 0 0 M00004146C:C11 5257 0 1 0 0 0 0M00004151D:B08 16977 0 0 0 0 0 0 M00004157C:A09 6455 0 0 0 0 0 0M00004169C:C12 5319 0 0 0 0 0 0 M00004171D:B03 4908 0 0 0 0 0 0M00004172C:D08 11494 0 0 0 0 0 0 M00004183C:D07 16392 0 0 0 0 0 0M00004185C:C03 11443 0 0 0 0 0 0 M00004197D:H01 8210 0 0 0 0 0 0M00004203B:C12 14311 0 0 0 0 0 0 M00004212B:C07 2379 0 0 0 0 0 0M00004214C:H05 11451 0 0 0 0 0 0 M00004223A:G10 16918 0 0 0 0 0 0M00004223B:D09 7899 0 0 0 0 0 0 M00004223D:E04 12971 0 0 0 0 0 0M00004229B:F08 6455 0 0 0 0 0 0 M00004230B:C07 7212 0 0 0 0 0 0M00004269D:D06 4905 0 0 0 0 0 0 M00004275C:C11 16914 0 0 0 0 0 0M00004283B:A04 14286 0 0 0 0 0 0 M00004285B:E08 56020 0 0 0 0 0 0M00004295D:F12 16921 0 0 0 0 0 0 M00004296C:H07 13046 0 0 0 0 0 0M00004307C:A06 9457 0 0 0 0 0 0 M00004312A:G03 26295 0 0 0 0 0 0M00004318C:D10 21847 0 0 0 0 0 0 M00004372A:A03 2030 0 0 0 0 0 0M00004377C:F05 2102 0 0 0 0 0 0

TABLE 7 Clones in Clones in Clones in Clone Name Cluster ID Lib12 Lib13Lib14 M00001340B:A06 17062 0 0 0 M00001340D:F10 11589 0 0 0M00001341A:E12 4443 4 2 0 M00001342B:E06 39805 0 0 0 M00001343C:F10 27900 0 0 M00001343D:H07 23255 0 0 0 M00001345A:E01 6420 0 0 0M00001346A:F09 5007 0 0 0 M00001346D:E03 6806 0 1 1 M00001346D:G06 57790 0 0 M00001346D:G06 5779 0 0 0 M00001347A:B10 13576 0 0 0M00001348B:B04 16927 0 0 0 M00001348B:G06 16985 0 0 0 M00001349B:B083584 0 0 0 M00001350A:H01 7187 0 0 0 M00001351B:A08 3162 0 0 1M00001351B:A08 3162 0 0 1 M00001352A:E02 16245 0 0 0 M00001353A:G12 80780 0 0 M00001353D:D10 14929 0 1 0 M00001355B:G10 14391 0 0 0M00001357D:D11 4059 0 0 0 M00001361A:A05 4141 1 2 1 M00001361D:F08 23790 0 0 M00001362B:D10 5622 0 2 1 M00001362C:H11 945 0 0 0 M00001365C:C1040132 0 0 0 M00001370A:C09 6867 0 0 0 M00001371C:E09 7172 0 0 1M00001376B:G06 17732 2 0 0 M00001378B:B02 39833 0 0 0 M00001379A:A051334 0 0 0 M00001380D:B09 39886 0 0 0 M00001382C:A02 22979 1 0 0M00001383A:C03 39648 0 0 0 M00001383A:C03 39648 0 0 0 M00001386C:B125178 0 0 0 M00001387A:C05 2464 0 0 0 M00001387B:G03 7587 0 0 0M00001388D:G05 5832 0 0 0 M00001389A:C08 16269 2 0 0 M00001394A:F01 65830 0 0 M00001395A:C03 4016 0 0 0 M00001396A:C03 4009 2 0 0 M00001402A:E0839563 0 0 0 M00001407B:D11 5556 0 0 0 M00001409C:D12 9577 0 0 0M00001410A:D07 7005 0 0 0 M00001412B:B10 8551 0 0 0 M00001415A:H06 135380 0 0 M00001416A:H01 7674 0 0 0 M00001416B:H11 8847 1 0 0 M00001417A:E0236393 0 0 0 M00001418B:F03 9952 0 0 0 M00001418D:B06 8526 0 0 0M00001421C:F01 9577 0 0 0 M00001423B:E07 15066 0 0 0 M00001424B:G0910470 0 0 0 M00001425B:H08 22195 0 0 0 M00001426D:C08 4261 0 0 0M00001428A:H10 84182 0 0 0 M00001429A:H04 2797 0 0 0 M00001429B:A11 46350 0 0 M00001429D:D07 40392 0 0 0 M00001439C:F08 40054 0 0 0M00001442C:D07 16731 0 0 0 M00001445A:F05 13532 0 0 0 M00001446A:F057801 0 1 0 M00001447A:G03 10717 0 0 0 M00001448D:C09 8 7 6 9M00001448D:H01 36313 1 0 0 M00001449A:A12 5857 0 0 0 M00001449A:B1241633 0 0 0 M00001449A:D12 3681 1 0 0 M00001449A:G10 36535 0 0 0M00001449C:D06 86110 0 0 0 M00001450A:A02 39304 0 1 0 M00001450A:A1132663 0 0 0 M00001450A:B12 82498 0 0 0 M00001450A:D08 27250 0 0 0M00001452A:B04 84328 0 0 0 M00001452A:B12 86859 0 0 0 M00001452A:D081120 0 0 0 M00001452A:F05 85064 0 0 0 M00001452C:B06 16970 1 0 0M00001453A:E11 16130 0 0 0 M00001453C:F06 16653 0 0 0 M00001454A:A0983103 0 0 0 M00001454B:C12 7005 0 0 0 M00001454D:G03 689 0 0 1M00001455A:E09 13238 0 0 0 M00001455B:E12 13072 0 0 0 M00001455D:F099283 0 0 0 M00001455D:F09 9283 0 0 0 M00001460A:F06 2448 0 0 0M00001460A:F12 39498 0 0 0 M00001461A:D06 1531 0 0 1 M00001463C:B11 1917 32 31 M00001465A:B11 10145 0 0 0 M00001466A:E07 4275 0 0 0M00001467A:B07 38759 0 0 0 M00001467A:D04 39508 0 0 0 M00001467A:D0816283 0 0 0 M00001467A:D08 16283 0 0 0 M00001467A:E10 39442 0 0 0M00001468A:F05 7589 0 0 0 M00001469A:C10 12081 0 0 0 M00001469A:H1219105 0 0 0 M00001470A:B10 1037 0 0 0 M00001470A:C04 39425 0 0 0M00001471A:B01 39478 0 0 0 M00001481D:A05 7985 0 0 0 M00001490B:C0418699 0 0 0 M00001494D:F06 7206 0 0 0 M00001497A:G02 2623 1 0 0M00001499B:A11 10539 0 1 0 M00001500A:C05 5336 0 0 0 M00001500A:E11 26231 0 0 M00001500C:E04 9443 0 0 0 M00001501D:C02 9685 0 0 0 M00001504C:A0710185 0 0 0 M00001504C:H06 6974 0 0 0 M00001504D:G06 6420 0 0 0M00001507A:H05 39168 0 0 0 M00001511A:H06 39412 0 0 0 M00001512A:A0939186 0 0 0 M00001512D:G09 3956 0 0 0 M00001513A:B06 4568 0 0 0M00001513C:E08 14364 0 0 0 M00001514C:D11 40044 0 0 0 M00001517A:B074313 0 0 0 M00001518C:B11 8952 0 0 0 M00001528A:C04 7337 1 2 2M00001528A:F09 18957 0 0 0 M00001528B:H04 8358 0 0 0 M00001531A:D0138085 0 0 0 M00001532B:A06 3990 0 0 0 M00001533A:C11 2428 0 0 0M00001534A:C04 16921 0 0 0 M00001534A:D09 5097 0 0 0 M00001534A:F09 53214 7 6 M00001534C:A01 4119 0 0 0 M00001535A:B01 7665 0 2 4 M00001535A:C0620212 0 0 0 M00001535A:F10 39423 0 0 0 M00001536A:B07 2696 0 0 0M00001536A:C08 39392 0 0 0 M00001537A:F12 39420 0 0 0 M00001537B:G073389 0 0 0 M00001540A:D06 8286 0 0 0 M00001541A:D02 3765 0 0 0M00001541A:F07 22085 0 0 0 M00001541A:H03 39174 0 0 0 M00001542A:A0922113 0 0 0 M00001542A:E06 39453 0 0 0 M00001544A:E03 12170 0 0 0M00001544A:G02 19829 0 0 0 M00001544B:B07 6974 0 0 0 M00001545A:C0319255 0 0 0 M00001545A:D08 13864 0 0 0 M00001546A:G11 1267 0 0 0M00001548A:E10 5892 0 1 0 M00001548A:H09 1058 1 3 0 M00001549A:B02 40150 1 0 M00001549A:D08 10944 1 0 0 M00001549B:F06 4193 0 0 0M00001549C:E06 16347 0 0 0 M00001550A:A03 7239 0 1 0 M00001550A:G01 51751 0 0 M00001551A:B10 6268 0 0 1 M00001551A:F05 39180 0 0 0M00001551A:G06 22390 0 0 1 M00001551C:G09 3266 0 0 0 M00001552A:B12 3076 11 4 M00001552A:D11 39458 0 0 0 M00001552B:D04 5708 0 0 0M00001553A:H06 8298 0 0 0 M00001553B:F12 4573 0 0 0 M00001553D:D10 228140 0 0 M00001555A:B02 39539 0 0 0 M00001555A:C01 39195 0 0 0M00001555D:G10 4561 0 0 0 M00001556A:C09 9244 0 1 0 M00001556A:F11 15770 0 2 M00001556A:H01 15855 1 1 0 M00001556B:C08 4386 3 0 1M00001556B:G02 11294 0 0 0 M00001557A:D02 7065 0 0 0 M00001557A:D02 70650 0 0 M00001557A:F01 9635 0 0 0 M00001557A:F03 39490 0 0 0M00001557B:H10 5192 0 0 0 M00001557D:D09 8761 0 0 0 M00001558B:H11 75140 0 0 M00001560D:F10 6558 0 0 0 M00001561A:C05 39486 0 0 0M00001563B:F06 102 2 1 2 M00001564A:B12 5053 0 0 0 M00001571C:H06 5749 00 0 M00001578B:E04 23001 0 0 0 M00001579D:C03 6539 0 0 0 M00001583D:A106293 0 0 0 M00001586C:C05 4623 0 0 0 M00001587A:B11 39380 0 0 0M00001594B:H04 260 1 0 0 M00001597C:H02 4837 1 0 0 M00001597D:C05 104700 0 0 M00001598A:G03 16999 4 2 6 M00001601A:D08 22794 0 0 0M00001604A:B10 1399 6 3 3 M00001604A:F05 39391 0 0 0 M00001607A:E1111465 0 0 0 M00001608A:B03 7802 0 0 0 M00001608B:E03 22155 0 0 0M00001614C:F10 13157 0 0 0 M00001617C:E02 17004 0 0 0 M00001619C:F1240314 0 0 0 M00001621C:C08 40044 0 0 0 M00001623D:F10 13913 0 0 0M00001624A:B06 3277 0 0 0 M00001624C:F01 4309 0 0 0 M00001630B:H09 52140 1 2 M00001644C:B07 39171 0 0 0 M00001645A:C12 19267 0 0 0M00001648C:A01 4665 0 0 0 M00001657D:C03 23201 0 0 0 M00001657D:F0876760 0 0 0 M00001662C:A09 23218 0 0 0 M00001663A:E04 35702 0 0 0M00001669B:F02 6468 0 0 0 M00001670C:H02 14367 0 0 0 M00001673C:H02 70150 0 0 M00001675A:C09 8773 0 0 0 M00001676B:F05 11460 2 0 0M00001677C:E10 14627 0 0 0 M00001677D:A07 7570 0 0 0 M00001678D:F12 44161 2 0 M00001679A:A06 6660 0 0 0 M00001679A:F10 26875 0 0 0M00001679B:F01 6298 0 0 0 M00001679C:F01 78091 0 0 0 M00001679D:D0310751 0 0 0 M00001679D:D03 10751 0 0 0 M00001680D:F08 10539 0 1 0M00001682C:B12 17055 0 0 0 M00001686A:E06 4622 0 0 0 M00001688C:F09 53820 0 0 M00001693C:G01 4393 0 0 0 M00001716D:H05 67252 0 0 0M00003741D:C09 40108 0 0 0 M00003747D:C05 11476 0 0 0 M00003759B:B09 6970 0 0 M00003762C:B08 17076 0 0 0 M00003763A:F06 3108 0 0 0M00003774C:A03 67907 0 0 0 M00003796C:D05 5619 0 1 0 M00003826B:A0611350 0 0 0 M00003833A:E05 21877 0 0 0 M00003837D:A01 7899 0 0 0M00003839A:D08 7798 0 0 0 M00003844C:B11 6539 0 0 0 M00003846B:D06 68740 0 0 M00003851B:D10 13595 0 0 0 M00003853A:D04 5619 0 1 0M00003853A:F12 10515 0 0 1 M00003856B:C02 4622 0 0 0 M00003857A:G10 33890 0 0 M00003857A:H03 4718 0 0 0 M00003871C:E02 4573 0 0 0 M00003875B:F0412977 0 0 0 M00003875B:F04 12977 0 0 0 M00003875C:G07 8479 1 0 0M00003876D:E12 7798 0 0 0 M00003879B:C11 5345 4 8 3 M00003879B:D10 315870 0 0 M00003879D:A02 14507 0 0 0 M00003885C:A02 13576 0 0 0M00003885C:A02 13576 0 0 0 M00003906C:E10 9285 0 0 0 M00003907D:A0939809 0 0 0 M00003907D:H04 16317 0 0 0 M00003909D:C03 8672 0 0 0M00003912B:D01 12532 0 0 0 M00003914C:F05 3900 0 1 0 M00003922A:E0623255 0 0 0 M00003958A:H02 18957 0 0 0 M00003958A:H02 18957 0 0 0M00003958C:G10 40455 0 0 0 M00003958C:G10 40455 0 0 0 M00003968B:F0624488 0 0 0 M00003970C:B09 40122 0 0 0 M00003974D:E07 23210 0 0 0M00003974D:H02 23358 0 0 0 M00003975A:G11 12439 0 0 0 M00003978B:G055693 0 0 0 M00003981A:E10 3430 0 0 0 M00003982C:C02 2433 2 4 0M00003983A:A05 9105 0 0 0 M00004028D:A06 6124 0 0 0 M00004028D:C05 400730 1 0 M00004031A:A12 9061 0 0 0 M00004031A:A12 9061 0 0 0 M00004035C:A0737285 0 0 0 M00004035D:B06 17036 0 0 0 M00004059A:D06 5417 0 0 0M00004068B:A01 3706 0 0 0 M00004072B:B05 17036 0 0 0 M00004081C:D1015069 0 0 0 M00004081C:D12 14391 0 0 0 M00004086D:G06 9285 0 0 0M00004087D:A01 6880 0 0 0 M00004093D:B12 5325 0 0 0 M00004093D:B12 53250 0 0 M00004105C:A04 7221 0 0 0 M00004108A:E06 4937 0 0 0 M00004111D:A086874 0 0 0 M00004114C:F11 13183 0 0 0 M00004138B:H02 13272 0 0 0M00004146C:C11 5257 0 0 1 M00004151D:B08 16977 0 0 0 M00004157C:A09 64550 0 0 M00004169C:C12 5319 0 0 0 M00004171D:B03 4908 0 0 0 M00004172C:D0811494 0 0 0 M00004183C:D07 16392 0 0 0 M00004185C:C03 11443 2 0 0M00004197D:H01 8210 0 0 0 M00004203B:C12 14311 0 0 0 M00004212B:C07 23790 0 0 M00004214C:H05 11451 0 0 0 M00004223A:G10 16918 0 0 0M00004223B:D09 7899 0 0 0 M00004223D:E04 12971 0 0 0 M00004229B:F08 64550 0 0 M00004230B:C07 7212 0 0 1 M00004269D:D06 4905 0 0 0 M00004275C:C1116914 0 0 0 M00004283B:A04 14286 0 0 0 M00004285B:E08 56020 0 0 0M00004295D:F12 16921 0 0 0 M00004296C:H07 13046 0 0 0 M00004307C:A069457 1 0 0 M00004312A:G03 26295 0 0 0 M00004318C:D10 21847 0 0 0M00004372A:A03 2030 0 0 0 M00004377C:F05 2102 0 0 0

Example 5 Polynucleotides Differentially Expressed in High MetastaticPotential Breast Cancer Cells Versus Low Metastatic Breast Cancer Cells

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential breast cancer tissue and low metastatic breast cancer cells.Expression of these sequences in breast cancer can be valuable indetermining diagnostic, prognostic and/or treatment information. Forexample, sequences that are highly expressed in the high metastaticpotential cells can be indicative of increased expression of genes orregulatory sequences involved in the metastatic process. A patientsample displaying an increased level of one or more of thesepolynucleotides may thus warrant more aggressive treatment. In anotherexample, sequences that display higher expression in the low metastaticpotential cells can be associated with genes or regulatory sequencesthat inhibit metastasis, and thus the expression of thesepolynucleotides in a sample may warrant a more positive prognosis thanthe gross pathology would suggest.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic marker, for risk assessment, patienttreatment and the like. These polynucleotide sequences can also be usedin combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides withdifferential expression between high metastatic potential breast cancercells and low metastatic potential breast cancer cells. TABLE 8Differentially expressed polynucleotides: High metastatic potentialbreast cancer vs. low metastatic breast cancer cells Clones in SEQCluster Clones in 2^(nd) ID NO. Differential Expression ID 1^(st)LibraryLibrary Ratio 9 High Breast > Low Breast (Lib3 > Lib4) 2623 31 47.561356 42 High Breast > Low Breast (Lib3 > Lib4) 307 196 75 2.54972152 High Breast > Low Breast (Lib3 > Lib4) 19 1364 525 2.534854 62 HighBreast > Low Breast (Lib3 > Lib4) 2623 31 4 7.561356 65 High Breast >Low Breast (Lib3 > Lib4) 5749 9 0 8.780930 66 High Breast > Low Breast(Lib3 > Lib4) 6455 6 0 5.853953 68 High Breast > Low Breast (Lib3 >Lib4) 6455 6 0 5.853953 114 High Breast > Low Breast (Lib3 > Lib4) 203032 4 7.805271 123 High Breast > Low Breast (Lib3 > Lib4) 3389 13 26.341782 144 High Breast > Low Breast (Lib3 > Lib4) 4623 12 2 5.853953172 High Breast > Low Breast (Lib3 > Lib4) 102 278 116 2.338217 178 HighBreast > Low Breast (Lib3 > Lib4) 3681 10 1 9.756589 214 High Breast >Low Breast (Lib3 > Lib4) 3900 8 1 7.805271 219 High Breast > Low Breast(Lib3 > Lib4) 3389 13 2 6.341782 223 High Breast > Low Breast (Lib3 >Lib4) 1399 19 7 2.648217 258 High Breast > Low Breast (Lib3 > Lib4) 483710 0 9.756589 317 High Breast > Low Breast (Lib3 > Lib4) 1577 25 38.130490 379 High Breast > Low Breast (Lib3 > Lib4) 260 27 2 13.17139 4Low Breast > High Breast (Lib4 > Lib3) 3706 22 4 5.637215 39 LowBreast > High Breast (Lib4 > Lib3) 4016 6 0 6.149690 74 Low Breast >High Breast (Lib4 > Lib3) 6268 18 3 6.149690 81 Low Breast > High Breast(Lib4 > Lib3) 40392 8 1 8.199586 130 Low Breast > High Breast (Lib4 >Lib3) 13183 7 0 7.174638 157 Low Breast > High Breast (Lib4 > Lib3) 54179 0 9.224535 162 Low Breast > High Breast (Lib4 > Lib3) 9685 7 07.174638 183 Low Breast > High Breast (Lib4 > Lib3) 7337 16 3 5.466391202 Low Breast > High Breast (Lib4 > Lib3) 6124 9 1 9.224535 298 LowBreast > High Breast (Lib4 > Lib3) 1037 22 4 5.637215 338 Low Breast >High Breast (Lib4 > Lib3) 689 36 17 2.170478 384 Low Breast > HighBreast (Lib4 > Lib3) 697 72 30 2.459876 386 Low Breast > High Breast(Lib4 > Lib3) 4568 9 0 9.224535 388 Low Breast > High Breast (Lib4 >Lib3) 5622 13 2 6.662164

Example 6 Polynucleotides Differentially Expressed in High MetastaticPotential Lung Cancer Cells Versus Low Metastatic Lung Cancer Cells

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential lung cancer tissue and low metastatic lung cancer cells.Expression of these sequences in lung cancer tissue can be valuable indetermining diagnostic, prognostic and/or treatment information. Forexample, sequences that are highly expressed in the high metastaticpotential cells are associated can be indicative of increased expressionof genes or regulatory sequences involved in the metastatic process. Apatient sample displaying an increased level of one or more of thesepolynucleotides may thus warrant more aggressive treatment. In anotherexample, sequences that display higher expression in the low metastaticpotential cells can be associated with genes or regulatory sequencesthat inhibit metastasis, and thus the expression of thesepolynucleotides in a sample may warrant a more positive prognosis thanthe gross pathology would suggest.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic marker, for risk assessment, patienttreatment and the like. These polynucleotide sequences can also be usedin combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides withdifferential expression between high metastatic potential lung cancercells and low metastatic potential lung cancer cells: TABLE 9Differentially expressed polynucleotides: High metastatic potential lungcancer vs. low metastatic lung cancer cells Clones in SEQ Cluster Clonesin 2^(nd) ID NO. Differential Expression ID 1^(st) Library Library Ratio400 High Lung > Low Lung (Lib8 > Lib 9) 14929 23 16 2.008868 9 HighLung > Low Lung (Lib8 > Lib9) 2623 6 1 8.384840 34 High Lung > Low Lung(Lib8 > Lib9) 5832 5 0 6.987366 42 High Lung > Low Lung (Lib8 > Lib9)307 79 27 4.088903 62 High Lung > Low Lung (Lib8 > Lib9) 2623 6 18.384840 74 High Lung > Low Lung (Lib8 > Lib9) 6268 5 0 6.987366 106High Lung > Low Lung (Lib8 > Lib9) 10717 8 0 11.17978 119 High Lung >Low Lung (Lib8 > Lib9) 8 1355 122 15.52111 361 High Lung > Low Lung(Lib8 > Lib9) 1120 5 0 6.987366 369 High Lung > Low Lung (Lib8 > Lib9)2790 6 0 8.384840 371 High Lung > Low Lung (Lib8 > Lib9) 8847 6 18.384840 379 High Lung > Low Lung (Lib8 > Lib9) 260 15 0 20.96210 395High Lung > Low Lung (Lib8 > Lib9) 13538 9 1 12.57726 135 Low Lung >High Lung (Lib9 > Lib8) 36313 30 1 21.46731 154 Low Lung > High Lung(Lib9 > Lib8) 5345 27 6 3.220097 160 Low Lung > High Lung (Lib9 > Lib8)4386 21 3 5.009039 260 Low Lung > High Lung (Lib9 > Lib8) 4141 27 44.830145 308 Low Lung > High Lung (Lib9 > Lib8) 15855 213 12 12.70149323 Low Lung > High Lung (Lib9 > Lib8) 5257 25 5 3.577885 349 Low Lung >High Lung (Lib9 > Lib8) 2797 14 1 10.01807 381 Low Lung > High Lung(Lib9 > Lib8) 2428 19 2 6.797982

Example 7 Polynucleotides Differentially Expressed in High MetastaticPotential Colon Cancer Cells Versus Low Metastatic Colon Cancer Cells

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential colon cancer tissue and low metastatic colon cancer cells.Expression of these sequences in colon cancer tissue can be valuable indetermining diagnostic, prognostic and/or treatment information. Forexample, sequences that are highly expressed in the high metastaticpotential cells can be indicative of increased expression of genes orregulatory sequences involved in the metastatic process. A patientsample displaying an increased level of one or more of thesepolynucleotides may thus warrant more aggressive treatment. In anotherexample, sequences that display higher expression in the low metastaticpotential cells can be associated with genes or regulatory sequencesthat inhibit metastasis, and thus the expression of thesepolynucleotides in a sample may warrant a more positive prognosis thanthe gross pathology would suggest.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic marker, for risk assessment, patienttreatment and the like. These polynucleotide sequences can also be usedin combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides withdifferential expression between high metastatic potential colon cancercells and low metastatic potential colon cancer cells: TABLE 10Differentially expressed polynucleotides: High metastatic potentialcolon cancer vs. low metastatic colon cancer cells Clones in SEQ ClusterClones in 2^(nd) ID NO. Differential Expression ID 1^(st) LibraryLibrary Ratio 1 High Colon > Low Colon (Lib1 > Lib2) 6660 7 0 6.489973176 High Colon > Low Colon (Lib1 > Lib2) 3765 19 6 2.935940 241 HighColon > Low Colon (Lib1 > Lib2) 4275 11 2 5.099264 362 High Colon > LowColon (Lib1 > Lib2) 6420 8 0 7.417112 374 High Colon > Low Colon (Lib1 >Lib2) 6420 8 0 7.417112 39 Low Colon > High Colon (Lib2 > Lib1) 4016 145 3.020043 97 Low Colon > High Colon (Lib2 > Lib1) 945 21 9 2.516702 134Low Colon > High Colon (Lib2 > Lib1) 2464 19 5 4.098630 317 Low Colon >High Colon (Lib2 > Lib1) 1577 40 12 3.595289 357 Low Colon > High Colon(Lib2 > Lib1) 4309 13 4 3.505407

Example 8 Polynucleotides Differentially Expressed at Higher Levels inHigh Metastatic Potential Colon Cancer Patient Tissue Versus NormalPatient Tissue

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential colon cancer tissue and normal tissue. Expression of thesesequences in colon cancer tissue can be valuable in determiningdiagnostic, prognostic and/or treatment information. For example,sequences that are highly expressed in the high metastatic potentialcells are associated can be indicative of increased expression of genesor regulatory sequences involved in the advanced disease state whichinvolves processes such as angiogenesis, dedifferentiation, cellreplication, and metastasis. A patient sample displaying an increasedlevel of one or more of these polynucleotides may thus warrant moreaggressive treatment.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic marker, for risk assessment, patienttreatment and the like. These polynucleotide sequences can also be usedin combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides withdifferential expression between high metastatic potential colon cancercells and normal colon cells: TABLE 11 Differentially expressedpolynucleotides: High metastatic potential colon tissue vs. normal colontissue Clones Clones SEQ Cluster in 1^(st) in 2^(nd) ID NO. DifferentialExpression ID Library Library Ratio 52 High Colon Metastasis 19 10 011.69918 Tissue > Normal Colon Tissue of UC#3 (Lib20 > Lib18) 52 HighColon Metastasis 19 13 2 6.025646 Tissue > Normal Tissue in UC#2(Lib17 > Lib15) 172 High Colon Metastasis 102 65 22 2.738930 Tissue >Normal Tissue in UC#2 (Lib17 > Lib15)

Example 9 Polynucleotides Differentially Expressed at Higher Levels inHigh Colon Tumor Potential Patient Tissue Versus Metastasized ColonCancer Patient Tissue

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high tumor potentialcolon cancer tissue and cells derived from high metastatic potentialcolon cancer cells. Expression of these sequences in colon cancer tissuecan be valuable in determining diagnostic, prognostic and/or treatmentinformation associated with the transformation of precancerous tissue tomalignant tissue. This information can be useful in the prevention ofachieving the advanced malignant state in these tissues, and can beimportant in risk assessment for a patient.

The following table summarizes identified polynucleotides withdifferential expression between high tumor potential colon cancer tissueand cells derived from high metastatic potential colon cancer cells:TABLE 12 Differentially expressed polynucleotides: High tumor potentialcolon tissue vs. metastatic colon tissue Clones Clones SEQ Cluster in1^(st) in 2^(nd) ID NO. Differential Expression ID Library Library Ratio52 High Colon Tumor 19 69 10 5.160829 Tissue > Metastasis Tissue of UC#3(Lib19 > Lib20) 119 High Colon Tumor 8 14 1 10.47124 Tissue > MetastasisTissue of UC#3 (Lib19 > Lib20) 172 High Colon Tumor 102 43 10 3.216168Tissue > Metastasis Tissue of UC#3 (Lib19 > Lib20)

Example 10 Polynucleotides Differentially Expressed at Higher Levels inHigh Tumor Potential Colon Cancer Patient Tissue Versus Normal PatientTissue

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high tumor potentialcolon cancer tissue and normal tissue. Expression of these sequences incolon cancer tissue can be valuable in determining diagnostic,prognostic and/or treatment information associated with the preventionof achieving the malignant state in these tissues, and can be importantin risk assessment for a patient. For example, sequences that are highlyexpressed in the potential colon cancer cells are associated with or canbe indicative of increased expression of genes or regulatory sequencesinvolved in early tumor progression. A patient sample displaying anincreased level of one or more of these polynucleotides may thus warrantcloser attention or more frequent screening procedures to catch themalignant state as early as possible.

The following table summarizes identified polynucleotides withdifferential expression between high metastatic potential colon cancercells and normal colon cells: TABLE 13 Differentially expressedpolynucleotides: High tumor potential colon tissue vs. normal colontissue Clones Clones SEQ Cluster in 1^(st) in 2^(nd) ID NO. DifferentialExpression ID Library Library Ratio 52 High Colon Tumor 19 13 2 6.255508Tissue > Normal Tissue of UC#2 (Lib16 > Lib15) 288 High Colon Tumor 12677 0 6.125253 Tissue > Normal Tissue of UC#2 (Lib16 > Lib15) 52 HighColon Tumor 19 69 0 60.37750 Tissue > Normal Tissue of UC#3 (Lib19 >Lib18) 119 High Colon Tumor 8 14 1 12.25050 Tissue > Normal Tissue ofUC#3 (Lib19 > Lib18) 172 High Colon Tumor 102 43 7 5.375222 Tissue >Normal Tissue of UC#3 (Lib19 > Lib18)

Example 11 Polynucleotides Differentially Expressed Across MultipleLibraries

A number of polynucleotide sequences have been identified that aredifferentially expressed between cancerous cells and normal cells acrossall three tissue types tested (i.e., breast, colon, and lung).Expression of these sequences in a tissue or any origin can be valuablein determining diagnostic, prognostic and/or treatment informationassociated with the prevention of achieving the malignant state in thesetissues, and can be important in risk assessment for a patient. Thesepolynucleotides can also serve as non-tissue specific markers of, forexample, risk of metastasis of a tumor. The following table summarizesidentified polynucleotides that were differentially expressed butwithout tissue type-specificity in the breast, colon, and lung librariestested. TABLE 14 Polynucleotides Differentially Expressed AcrossMultiple Library Comparisons Clones in Clones in SEQ Cluster 1^(st)2^(nd) ID NO. Differential Expression ID Library Library Ratio 9 HighBreast > Low Breast (Lib3 > Lib4) 2623 31 4 7.561356 High Lung > LowLung (Lib8 > Lib9) 2623 6 1 8.384840 39 Low Breast > High Breast (Lib4 >Lib3) 4016 6 0 6.149690 Low Colon > High Colon (Lib2 > Lib1) 4016 14 53.020043 42 High Breast > Low Breast (Lib3 > Lib4) 307 196 75 2.549721High Lung > Low Lung (Lib8 > Lib9) 307 79 27 4.088903 52 High Breast >Low Breast (Lib3 > Lib4) 19 1364 525 2.534854 High Colon MetastasisTissue > Normal 19 10 0 11.69918 Colon Tissue of UC#3 (Lib20 > Lib18)High Colon Metastasis Tissue > Normal 19 13 2 6.025646 Tissue in UC#2(Lib17 > Lib15) High Colon Tumor Tissue > Metastasis 19 69 10 5.160829Tissue of UC#3 (Lib 19 > Lib20) High Colon Tumor Tissue > Normal 19 13 26.255508 Tissue of UC#2 (Lib16 > Lib15) High Colon Tumor Tissue > Normal19 69 0 60.37750 Tissue of UC#3 (Lib19 > Lib18) 62 High Breast > LowBreast (Lib3 > Lib4) 2623 31 4 7.561356 High Lung > Low Lung (Lib8 >Lib9) 2623 6 1 8.384840 74 High Lung > Low Lung (Lib8 > Lib9) 6268 5 06.987366 Low Breast > High Breast (Lib4 > Lib3) 6268 18 3 6.149690 119High Colon Tumor Tissue > Metastasis 8 14 1 10.47124 Tissue of UC#3(Lib19 > Lib20) High Colon Tumor Tissue > Normal 8 14 1 12.25050 Tissueof UC#3 (Lib19 > Lib18) High Lung > Low Lung (Lib8 > Lib9) 8 1355 12215.52111 172 High Breast > Low Breast (Lib3 > Lib4) 102 278 116 2.338217High Colon Metastasis Tissue > Normal 102 65 22 2.738930 Tissue in UC#2(Lib17 > Lib15) High Colon Tumor Tissue > Metastasis 102 43 10 3.216168Tissue of UC#3 (Lib19 > Lib20) High Colon Tumor Tissue > Normal 102 43 75.375222 Tissue of UC#3 (Lib19 > Lib18) 317 High Breast > Low Breast(Lib3 > Lib4) 1577 25 3 8.130490 Low Colon > High Colon (Lib2 > Lib1)1577 40 12 3.595289 379 High Breast > Low Breast (Lib3 > Lib4) 260 27 213.17139 High Lung > Low Lung (Lib8 > Lib9) 260 15 0 20.96210

Example 12 Polynucleotides Exhibiting Colon-Specific Expression

The cDNA libraries described herein were also analyzed to identify thosepolynucleotides that were specifically expressed in colon cells ortissue, i.e., the polynucleotides were identified in libraries preparedfrom colon cell lines or tissue, but not in libraries of breast or lungorigin. The polynucleotides that were expressed in a colon cell lineand/or in colon tissue, but were present in the breast or lung cDNAlibraries described herein, are shown in Table 15. TABLE 15Polynucleotides specifically expressed in colon cells. Clones Clones SEQID in 1^(st) in 2^(nd) NO. Cluster Library Library 5 36535 2 0 13 272502 0 19 16283 3 0 24 16918 4 0 26 40108 2 0 32 32663 1 1 43 39833 2 0 4718957 3 0 48 39508 2 0 56 7005 8 2 58 18957 3 0 59 18957 3 0 60 16283 30 64 13238 4 1 70 39442 2 0 71 17036 4 0 73 7005 8 2 83 11476 6 0 8639425 2 0 94 21847 2 1 100 16731 3 1 101 12439 4 0 113 17055 4 0 12067907 1 0 121 12081 4 0 124 39174 2 0 126 8210 2 6 128 40455 2 0 13922195 3 0 143 86859 1 0 150 8672 4 4 153 16977 4 0 156 17036 4 0 15940044 2 0 161 40044 2 0 163 22155 3 0 166 15066 4 0 170 11465 5 0 1763765 19 6 181 86110 1 0 182 39648 2 0 185 17076 4 0 186 22794 2 0 18739171 2 0 194 40455 2 0 199 16317 3 0 210 39186 2 0 211 40122 2 0 21826295 2 0 222 4665 5 9 226 82498 1 0 227 35702 2 0 229 39648 2 0 23185064 1 0 234 39391 2 0 236 39498 2 0 242 22113 3 0 247 19255 2 0 25222814 3 0 253 39563 2 0 254 39420 2 0 257 39412 2 0 261 38085 2 0 26540054 1 0 266 39423 2 0 267 39453 2 0 270 78091 1 0 276 39168 2 0 27739458 2 0 278 14391 3 1 279 39195 2 0 282 12977 5 0 284 14391 3 1 29016347 4 0 293 39478 2 0 294 39392 2 0 297 39180 2 0 299 6867 7 3 30141633 1 1 302 23218 3 0 303 39380 2 0 309 84328 1 0 314 14367 3 0 32039886 2 0 324 9061 5 2 327 16653 3 1 328 16985 4 0 329 12977 5 0 3309061 5 2 333 16392 3 0 342 39486 2 0 344 6874 6 3 345 6874 6 3 353 114944 0 354 17062 3 0 355 16245 4 0 356 83103 1 0 358 13072 4 1 366 14364 10 368 84182 1 0 372 56020 1 0 89 7514 5 3 391 7570 5 3 393 23210 3 0

In addition to the above, SEQ ID NOS:159 and 161 were each present inone clone in each of Lib16 (Normal Colon Tumor Tissue), and SEQ IDNOS:344 and 345 were each present in one clone in Lib17 (High ColonMetastasis Tissue). No clones corresponding to the colon-specificpolynucleotides in the table above were present in any of Libraries 3,4, 8, or 9. The polynucleotide provided above can be used as markers ofcells of colon origin, and find particular use in reference arrays, asdescribed above.

Example 13 Identification of Contiguous Sequences having aPolynucleotide of the Invention

The novel polynucleotides were used to screen publicly available andproprietary databases to determine if any of the polynucleotides of SEQID NOS:1-404 would facilitate identification of a contiguous sequence,e.g., the polynucleotides would provide sequence that would result in 5′extension of another DNA sequence, resulting in production of a longercontiguous sequence composed of the provided polynucleotide and theother DNA sequence(s). Contiging was performed using the AssemblyLignprogram with the following parameters: 1) Overlap: Minimum OverlapLength: 30; % Stringency: 50; Minimum Repeat Length: 30; Alignment: gapcreation penalty: 1.00, gap extension penalty: 1.00; 2) Consensus: %Base designation threshold: 80.

Using these parameters, 44 polynucleotides provided contiged sequences.These contiged sequences are provided as SEQ ID NOS:801-844. Thecontiged sequences can be correlated with the sequences of SEQ IDNOS:1-404 upon which the contiged sequences are based by identifyingthose sequences of SEQ ID NOS:1-404 and the contiged sequences of SEQ IDNOS:801-844 that share the same clone name in Table 1. It should benoted that of these 44 sequences that provided a contiged sequence, thefollowing members of that group of 44 did not contig using the overlapsettings indicated in parentheses (Stringency/Overlap): SEQ ID NO:804(30%/10); SEQ ID NO:810 (20%/20); SEQ ID NO:812 (30%/10); SEQ ID NO:814(40%/20); SEQ ID NO:816 (30%/10); SEQ ID NO:832 (30%/10); SEQ ID NO:840(20%/20); SEQ ID NO:841 (40%/20). To generalize, the indicatedpolynucleotides did not contig using a minimum 20% stringency, 10overlap. There was a corresponding increase in the number of degeneratecodons in these sequences.

The contiged sequences (SEQ ID NO:801-844) thus represent longersequences that encompass a polynucleotide sequence of the invention. Thecontiged sequences were then translated in all three reading frames todetermine the best alignment with individual sequences using the BLASTprograms as described above for SEQ ID NOS:1-404 and the validationsequences SEQ ID NOS:405-800. Again the sequences were masked using theXBLAST profram for masking low complexity as described above in Example1 (Table 2). Several of the contiged sequences were found to encodepolypeptides having characteristics of a polypeptide belonging to aknown protein families (and thus represent new members of these proteinfamilies) and/or comprising a known functional domain (Table 16). Thusthe invention encompasses fragments, fusions, and variants of suchpolynucleotides that retain biological activity associated with theprotein family and/or functional domain identified herein. TABLE 16Profile hits using contiged sequences SEQ ID Start NO. Sequence NameProfile (Stop) Score 809 Contig_RTA00000177AF.n.18.3.Seq_THC123051ATPases  778 6040 (1612) 824 Contig_RTA00000187AF.g.24.1.Seq_THC168636homeobox  531 12080  (707) 824 Contig_RTA00000187AF.g.24.1.Seq_THC168636MAP kinase  769 5784 kinase (1494) 833Contig_RTA00000190AF.j.4.1.Seq_THC228776 protein kinase  170 5027 (1010)833 Contig_RTA00000190AF.j.4.1.Seq_THC228776 protein kinase  170 5027(1010)All stop/start sequences are provided in the forward direction.

The profiles for the ATPases (AAA) and protein kinase families aredescribed above in Example 2. The homeobox and MAP kinase kinase proteinfamilies are described further below.

Homeobox domain. The ‘homeobox’ is a protein domain of 60 amino acids(Gehring In: Guidebook to the Homeobox Genes, Duboule D., Ed., pp1-10,Oxford University Press, Oxford, (1994); Buerglin In: Guidebook to theHomeobox Genes, pp25-72, Oxford University Press, Oxford, (1994);Gehring Trends Biochem. Sci. (1992) 17:277-280; Gehring et al Annu. Rev.Genet. (1986) 20:147-173; Schofield Trends Neurosci. (1987) 10:3-6;http://copan.bioz.unibas.ch/homeo.html) first identified in number ofDrosophila homeotic and segmentation proteins. It is extremely wellconserved in many other animals, including vertebrates. This domainbinds DNA through a helix-turn-helix type of structure. Several proteinsthat contain a homeobox domain play an important role in development.Most of these proteins are sequence-specific DNA-binding transcriptionfactors. The homeobox domain is also very similar to a region of theyeast mating type proteins. These are sequence-specific DNA-bindingproteins that act as master switches in yeast differentiation bycontrolling gene expression in a cell type-specific fashion.

A schematic representation of the homeobox domain is shown below. Thehelix-turn-helix region is shown by the symbols ‘H’ (for helix), and ‘t’(for turn).

The pattern detects homeobox sequences 24 residues long and spanspositions 34 to 57 of the homeobox domain.

MAP kinase kinase (MAPKK). MAP kinases (MAPK) are involved in signaltransduction, and are important in cell cycle and cell growth controls.The MAP kinase kinases (MAPKK) are dual-specificity protein kinaseswhich phosphorylate and activate MAP kinases. MAPKK homologues have beenfound in yeast, invertebrates, amphibians, and mammals. Moreover, theMAPKK/MAPK phosphorylation switch constitutes a basic module activatedin distinct pathways in yeast and in vertebrates. MAPKK regulationstudies have led to the discovery of at least four MAPKK convergentpathways in higher organisms. One of these is similar to the yeastpheromone response pathway which includes the ste11 protein kinase. Twoother pathways require the activation of either one or both of theserine/threonine kinase-encoded oncogenes c-Raf-1 and c-Mos.Additionally, several studies suggest a possible effect of the cellcycle control regulator cyclin-dependent kinase 1 (cdc2) on MAPKKactivity. Finally, MAPKKs are apparently essential transducers throughwhich signals must pass before reaching the nucleus. For review, see,e.g., Biologique Biol Cell (1993) 79:193-207; Nishida et al., TrendsBiochem Sci (1993) 18:128-31; Ruderman Curr Opin Cell Biol (1993)5:207-13; Dhanasekaran et al., Oncogene (1998) 17:1447-55; Kiefer etal., Biochem Soc Trans (1997) 25:491-8; and Hill, Cell Signal (1996)8:533-44.

Those skilled in the art will recognize, or be able to ascertain, usingnot more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such specific embodimentsand equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Deposit Information:

The following materials were deposited with the American Type CultureCollection: CMCC=(Chiron Master Culture Collection) Cell Lines Depositedwith ATCC Cell Line Deposit Date ATCC Accession No. CMCC Accession No.KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-1253311611 MDA-MB-231 May 15, 1998 CRL-12532 10583 MCF-7 Oct. 9, 1998CRL-12584 10377 CDNA Library Deposits Clone Name Cluster ID SequenceName cDNA Library ES1 - ATCC# 207023 Deposit Date - Dec. 22, 1998M00001395A:C03 4016 79.A1.sp6:130016.Seq M00001395A:C03 4016RTA00000118A.c.4.1 M00001449A:D12 3681 RTA00000131A.g.15.2M00001449A:D12 3681 79.E1.sp6:130064.Seq M00001452A:D08 112079.C2.sp6:130041.Seq M00001452A:D08 1120 RTA00000118A.p.15.3M00001513A:B06 4568 79.D4.sp6:130055.Seq M00001513A:B06 4568RTA00000122A.d.15.3 M00001517A:B07 4313 79.F4.sp6:130079.SeqM00001517A:B07 4313 RTA00000122A.n.3.1 M00001533A:C11 2428RTA00000123A.1.21.1 M00001533A:C11 2428 79.A5.sp6:130020.SeqM00001533A:C11 2428 RTA00000123A.1.21.1.Seq_THC205063 M00001542A:A0922113 79.F5.sp6:130080.Seq M00001542A:A09 22113 RTA00000125A.c.7.1 cDNALibrary ES2 - ATCC# 207024 Deposit Date - Dec. 22, 1998 M00001343C:F102790 80.E1.sp6:130256.Seq M00001343C:F10 2790RTA00000177AF.e.2.1.Seq_THC229461 M00001343C:F10 2790RTA00000177AF.e.2.1 M00001343D:H07 23255 100.C1.sp6:131446.SeqM00001343D:H07 23255 RTA00000177AF.e.14.3.Seq_THC228776 M00001343D:H0723255 80.F1.sp6:130268.Seq M00001343D:H07 23255 RTA00000177AF.e.14.3M00001345A:E01 6420 172.E1.sp6:133925.Seq M00001345A:E01 6420RTA00000177AF.f.10.3 M00001345A:E01 6420RTA00000177AF.f.10.3.Seq_THC226443 M00001345A:E01 642080.G1.sp6:130280.Seq M00001347A:B10 13576 80.D2.sp6:130245.SeqM00001347A:B10 13576 100.E1.sp6:131470.Seq M00001347A:B10 13576RTA00000177AF.g.16.1 M00001353A:G12 8078 80.E3.sp6:130258.SeqM00001353A:G12 8078 RTA00000177AR.l.13.1 M00001353A:G12 8078172.C3.sp6:133903.Seq M00001353D:D10 14929 RTA00000177AF.m.1.2M00001353D:D10 14929 80.F3.sp6:130270.Seq M00001353D:D10 14929172.D3.sp6:133915.Seq M00001361A:A05 4141 80.B4.sp6:130223.SeqM00001361A:A05 4141 RTA00000177AF.p.20.3 M00001362B:D10 562280.D4.sp6:130247.Seq M00001362B:D10 5622 RTA00000178AF.a.11.1 cDNALibrary ES3 - ATCC# 207025 Deposit Date - Dec. 22, 1998 M00001362C:H11945 RTA00000178AR.a.20.1 M00001362C:H11 945 100.E4.sp6:131473.SeqM00001362C:H11 945 80.E4.sp6:130259.Seq M00001362C:H11 945180.C2.sp6:135940.Seq M00001376B:G06 17732 RTA00000178AR.i.2.2M00001376B:G06 17732 80.B5.sp6:130224.Seq M00001387A:C05 246480.D6.sp6:130249.Seq M00001387A:C05 2464 RTA00000178AF.n.18.1M00001412B:B10 8551 RTA00000179AF.p.21.1 M00001412B:B10 855180.G7.sp6:130286.Seq M00001415A:H06 13538 80.B8.sp6:130227.SeqM00001415A:H06 13538 RTA00000180AF.a.24.1 M00001416B:H11 884780.C8.sp6:130239.Seq M00001416B:H11 8847 RTA00000180AF.b.16.1M00001429D:D07 40392 RTA00000180AF.j.8.1 M00001429D:D07 4039280.H9.sp6:130300.Seq M00001448D:H01 36313 80.A11.sp6:130218.SeqM00001448D:H01 36313 RTA00000181AF.e.23.1 cDNA Library ES4 - ATCC#207026 Deposit Date - Dec. 22, 1998 M00001463C:B11 19RTA00000182AF.b.7.1 M00001463C:B11 19 89.D1.sp6:130703.SeqM00001470A:B10 1037 89.F2.sp6:130728.Seq M00001470A:B10 1037RTA00000121A.f.8.1 M00001497A:G02 2623 89.F3.sp6:130729.SeqM00001497A:G02 2623 RTA00000183AF.a.6.1 M00001500A:E11 2623RTA00000183AF.b.14.1 M00001500A:E11 2623 89.A4.sp6:130670.SeqM00001501D:C02 9685 RTA00000183AF.c.11.1.Seq_THC109544 M00001501D:C029685 RTA00000183AF.c.11.1 M00001501D:C02 9685 89.C4.sp6:130694.SeqM00001504C:H06 6974 89.F4.sp6:130730.Seq M00001504C:H06 6974RTA00000183AF.d.9.1 M00001504C:H06 6974RTA00000183AF.d.9.1.Seq_THC223129 M00001504D:G06 6420173.F5.SP6:134133.Seq M00001504D:G06 6420 89.G4.sp6:130742.SeqM00001504D:G06 6420 RTA00000183AF.d.11.1.Seq_THC226443 M00001504D:G066420 RTA00000183AF.d.11.1 M00001528A:C04 35555 89.B6.sp6:130684.SeqM00001528A:C04 7337 RTA00000123A.b.17.1 M00001528A:C04 35555184.A5.sp6:135530.Seq cDNA Library ES5 - ATCC# 207027 Deposit Date -Dec. 22, 1998 M00001537B:G07 3389 RTA00000183AF.m.19.1 M00001537B:G073389 89.A8.sp6:130674.Seq M00001541A:D02 3765 89.C8.sp6:130698.SeqM00001541A:D02 3765 RTA00000135A.d.1.1 M00001544B:B07 697489.A9.sp6:130675.Seq M00001544B:B07 6974 RTA00000184AF.a.15.1M00001546A:G11 1267 89.D9.sp6:130711.Seq M00001546A:G11 1267RTA00000125A.o.5.1 M00001549B:F06 4193 89.G9.sp6:130747.SeqM00001549B:F06 4193 RTA00000184AF.e.13.1 M00001556A:F11 1577173.C9.SP6:134101.Seq M00001556A:F11 1577 89.F11.sp6:130737.SeqM00001556A:F11 1577 RTA00000184AF.i.23.1 M00001556B:C08 4386RTA00000184AF.j.4.1 M00001556B:C08 4386 89.H11.sp6:130761.Seq cDNALibrary ES6 - ATCC# 207028 Deposit Date - Dec. 22, 1998 M00001563B:F06102 RTA00000184AF.o.5.1 M00001563B:F06 102 90.B1.sp6:130871.SeqM00001571C:H06 5749 90.E1.sp6:130907.Seq M00001571C:H06 5749RTA00000185AF.a.19.1 M00001594B:H04 260 90.D2.sp6:130896.SeqM00001594B:H04 260 RTA00000185AR.i.12.2 M00001597C:H02 483790.E2.sp6:130908.Seq M00001597C:H02 4837 RTA00000185AR.k.3.2M00001624C:F01 4309 90.C4.sp6:130886.Seq M00001624C:F01 4309RTA00000186AF.e.22.1 M00001679A:A06 6660 90.F6.sp6:130924.SeqM00001679A:A06 6660 122.B5.sp6:132089.Seq M00001679A:A06 6660RTA00000187AF.h.15.1 M00003759B:B09 697 90.G8.sp6:130938.SeqM00003759B:B09 697 RTA00000188AF.d.6.1 M00003759B:B09 697RTA00000188AF.d.6.1.Seq_THC178884 M00003844C:B11 6539176.D9.sp6:134556.Seq M00003844C:B11 6539 RTA00000189AF.d.22.1M00003844C:B11 6539 90.B10.sp6:130880.Seq M00003857A:G10 338990.A11.sp6:130869.Seq M00003857A:G10 3389 RTA00000189AF.g.3.1 cDNALibrary ES7 - ATCC# 207029 Deposit Date - Dec. 22, 1998 M00003914C:F053900 99.E1.sp6:131278.Seq M00003914C:F05 3900 RTA00000190AF.g.13.1M00003922A:E06 23255 RTA00000190AF.j.4.1 M00003922A:E06 2325599.F1.sp6:131290.Seq M00003922A:E06 23255RTA00000190AF.j.4.1.Seq_THC228776 M00003983A:A05 910599.C3.sp6:131256.Seq M00003983A:A05 9105 RTA00000191AF.a.21.2M00004028D:A06 6124 RTA00000191AR.e.2.3 M00004028D:A06 612499.D3.sp6:131268.Seq M00004031A:A12 9061 RTA00000191AR.e.11.2M00004031A:A12 9061 RTA00000191AR.e.11.3 M00004087D:A01 6880RTA00000191AF.m.20.1 M00004087D:A01 6880 99.A5.sp6:131234.SeqM00004108A:E06 4937 99.E5.sp6:131282.Seq M00004108A:E06 4937RTA00000191AF.p.21.1 M00004114C:F11 13183 123.D5.sp6:132305.SeqM00004114C:F11 13183 RTA00000192AF.a.24.1 M00004114C:F11 1318399.G5.sp6:131306.Seq cDNA Library ES8 - ATCC# 207030 Deposit Date - Dec.22, 1998 M00004146C:C11 5257 99.B6.sp6:131247.Seq M00004146C:C11 5257177.F5.sp6:134768.Seq M00004146C:C11 5257 RTA00000192AF.f.3.1M00004146C:C11 5257 RTA00000192AF.f.3.1.Seq_THC213833 M00004157C:A096455 RTA00000192AF.g.23.1 M00004157C:A09 6455 99.D6.sp6:131271.SeqM00004157C:A09 6455 123.E7.sp6:132319.Seq M00004172C:D08 11494RTA00000192AF.j.6.1 M00004172C:D08 11494 99.G6.sp6:131307.SeqM00004172C:D08 11494 177.E6.sp6:134757.Seq M00004229B:F08 6455RTA00000193AF.b.9.1 M00004229B:F08 6455 99.C8.sp6:131261.Seq cDNALibrary ES9 - ATCC# 207031 Deposit Date - Dec. 22, 1998 M00001466A:E074275 RTA00000120A.j.14.1 M00001531A:H11 89.F6.sp6:130732.SeqM00001531A:H11 RTA00000123A.g.19.1 M00001551A:B10 626879.G9.sp6:130096.Seq M00001551A:B10 6268 184.C12.sp6:135561.SeqM00001551A:B10 6268 RTA00000126A.o.23.1 M00001552A:B12 307RTA00000136A.o.4.2 M00001552A:B12 307 79.C7.sp6:130046.SeqM00001556A:H01 15855 RTA00000184AF.j.1.1 M00001586C:C05 4623RTA00000185AF.f.4.1 M00001604A:B10 1399 79.G8.sp6:130095.SeqM00001604A:B10 1399 RTA00000129A.o.10.1 M00003879B:C11 5345RTA00000189AF.1.19.1 M00003879B:C11 5345 90.B12.sp6:130882.Seq cDNALibrary ES10 - ATCC#207032 Deposit Date - Dec. 22, 1998 M00001358C:C06RTA00000177AF.o.4.3 M00001388D:G05 5832 80.F6.sp6:130273.SeqM00001388D:G05 5832 RTA00000178AF.o.23.1 M00001394A:F01 6583RTA00000179AF.d.13.1 M00001394A:F01 6583 172.B8.sp6:133896.SeqM00001394A:F01 6583 80.H6.sp6:130297.Seq M00001429A:H04 2797RTA00000180AF.i.19.1 M00001447A:G03 10717 RTA00000181AF.d.10.1M00001448D:C09 8 80.H10.sp6:130301.Seq M00001448D:C09 8RTA00000181AF.e.17.1 M00001448D:C09 8 100.B11.sp6:131444.SeqM00001454D:G03 689 RTA00000181AR.1.22.1 cDNA Library ES11 - ATCC#207033Deposit Date - Dec. 22, 1998 M00003975A:G11 12439 RTA00000190AF.o.24.1M00003978B:G05 5693 RTA00000190AF.p.17.2.Seq_THC173318 M00003978B:G055693 RTA00000190AF.p.17.2 M00004059A:D06 5417 RTA00000191AF.h.19.1M00004068B:A01 3706 99.C4.sp6:131257.Seq M00004068B:A01 3706RTA00000191AF.i.17.2 M00004205D:F06 99.E7.sp6:131284.Seq M00004205D:F06177.G7.sp6:134782.Seq M00004205D:F06 RTA00000192AF.o.11.1 M00004212B:C072379 RTA00000192AF.p.8.1 M00004223A:G10 16918 RTA00000193AF.a.16.1 cDNALibrary ES12 - ATCC# 207034 Deposit Date - Dec. 22, 1998 M00004223B:D097899 RTA00000193AF.a.17.1 M00004249D:G12 RTA00000193AF.c.22.1M00004251C:G07 RTA00000193AF.d.2.1 M00004372A:A03 2030RTA00000193AF.m.20.1 cDNA Library ES13 - ATCC#207035 Deposit Date - Dec.22, 1998 M00001340B:A06 17062 80.A1.sp6:130208.Seq M00001340B:A06 17062RTA00000177AF.b.8.4 M00001340D:F10 11589 80.B1.sp6:130220.SeqM00001340D:F10 11589 RTA00000177AF.b.17.4 M00001341A:E12 444380.C1.sp6:130232.Seq M00001341A:E12 4443 RTA00000177AF.b.20.4M00001342B:E06 39805 80.D1.sp6:130244.Seq M00001342B:E06 39805RTA00000177AF.c.21.3 M00001346A:F09 5007 RTA00000177AF.g.2.1M00001346A:F09 5007 80.H1.sp6:130292.Seq M00001346D:G06 5779RTA00000177AF.g.14.3 M00001346D:G06 5779 RTA00000177AF.g.14.1M00001348B:B04 16927 80.E2.sp6:130257.Seq M00001348B:B04 16927RTA00000177AF.h.9.3 M00001348B:G06 16985 RTA00000177AF.h.10.1M00001348B:G06 16985 80.F2.sp6:130269.Seq M00001349B:B08 3584RTA00000177AF.h.20.1 M00001349B:B08 3584 80.G2.sp6:130281.SeqM00001350A:H01 7187 100.C2.sp6:131447.Seq M00001350A:H01 718780.A3.sp6:130210.Seq M00001350A:H01 7187 RTA00000177AF.i.8.2M00001352A:E02 16245 RTA00000177AF.k.9.3 M00001352A:E02 16245172.D2.sp6:133914.Seq M00001352A:E02 16245 80.D3.sp6:130246.SeqM00001355B:G10 14391 RTA00000177AF.m.17.3 M00001355B:G10 1439180.G3.sp6:130282.Seq M00001355B:G10 14391 172.H3.sp6:133963.SeqM00001355B:G10 14391 100.E3.sp6:131472.Seq M00001361D:F08 237980.C4.sp6:130235.Seq M00001361D:F08 2379 RTA00000178AF.a.6.1M00001365C:C10 40132 RTA00000178AF.c.7.1 M00001365C:C10 4013280.F4.sp6:130271.Seq M00001368D:E03 80.G4.sp6:130283.Seq M00001368D:E03RTA00000178AF.d.20.1 M00001370A:C09 6867 80.H4.sp6:130295.SeqM00001370A:C09 6867 RTA00000178AF.e.12.1 M00001371C:E09 7172100.A5.sp6:131426.Seq M00001371C:E09 7172 RTA00000178AF.f.9.1M00001371C:E09 7172 80.A5.sp6:130212.Seq M00001378B:B02 3983380.C5.sp6:130236.Seq M00001378B:B02 39833 RTA00000178AF.i.23.1M00001379A:A05 1334 80.D5.sp6:130248.Seq M00001379A:A05 1334RTA00000178AF.j.7.1 M00001380D:B09 39886 RTA00000178AF.j.24.1M00001380D:B09 39886 80.E5.sp6:130260.Seq M00001381D:E0680.F5.sp6:130272.Seq M00001381D:E06 RTA00000178AF.k.16.1 M00001382C:A0222979 80.G5.sp6:130284.Seq M00001382C:A02 22979 RTA00000178AF.k.22.1M00001384B:A11 80.B6.sp6:130225.Seq M00001384B:A11 RTA00000178AF.m.13.1M00001386C:B12 5178 80.C6.sp6:130237.Seq M00001386C:B12 5178RTA00000178AF.n.10.1 M00001387B:G03 7587 80.E6.sp6:130261.SeqM00001387B:G03 7587 RTA00000178AF.n.24.1 M00001389A:C08 16269RTA00000178AF.p.1.1 M00001389A:C08 16269 80.G6.sp6:130285.SeqM00001396A:C03 4009 172.D8.sp6:133920.Seq M00001396A:C03 400980.A7.sp6:130214.Seq M00001396A:C03 4009 RTA00000179AF.e.20.1M00001400B:H06 172.B9.sp6:133897.Seq M00001400B:H06 80.B7.sp6:130226.SeqM00001400B:H06 RTA00000179AF.j.13.1 M00001400B:H06RTA00000179AF.j.13.1.Seq_THC105720 M00001402A:E08 3956380.C7.sp6:130238.Seq M00001402A:E08 39563 RTA00000179AF.k.20.1M00001407B:D11 5556 RTA00000179AF.n.10.1 M00001407B:D11 555680.D7.sp6:130250.Seq M00001410A:D07 7005 180.H5.sp6:136003.SeqM00001410A:D07 7005 RTA00000179AF.o.22.1 M00001410A:D07 700580.F7.sp6:130274.Seq M00001414A:B01 RTA00000180AF.a.9.1 M00001414A:B0180.H7.sp6:130298.Seq M00001414C:A07 80.A8.sp6:130215.Seq M00001414C:A07RTA00000180AF.a.11.1 M00001416A:H01 7674 79.C1.sp6:130040.SeqM00001416A:H01 7674 RTA00000118A.g.9.1 M00001417A:E02 36393RTA00000180AF.c.2.1 M00001417A:E02 36393 80.D8.sp6:130251.SeqM00001423B:E07 15066 RTA00000180AF.e.24.1 M00001423B:E07 1506680.H8.sp6:130299.Seq M00001424B:G09 10470 80.A9.sp6:130216.SeqM00001424B:G09 10470 RTA00000180AF.f.18.1 M00001425B:H08 22195RTA00000180AF.g.7.1 M00001425B:H08 22195 80.B9.sp6:130228.SeqM00001426B:D12 RTA00000180AF.g.22.1 M00001426B:D12 80.C9.sp6:130240.SeqM00001426D:C08 4261 80.D9.sp6:130252.Seq M00001426D:C08 4261RTA00000180AF.h.5.1 M00001428A:H10 84182 100.G9.sp6:131502.SeqM00001428A:H10 84182 RTA00000180AF.h.19.1 M00001428A:H10 8418280.E9.sp6:130264.Seq M00001449A:A12 5857 80.B11.sp6:130230.SeqM00001449A:A12 5857 RTA00000118A.g.14.1 M00001449A:B12 4163380.C11.sp6:130242.Seq M00001449A:B12 41633 RTA00000118A.g.16.1M00001449A:G10 36535 RTA00000181AF.f.5.1 M00001449A:G10 3653580.D11.sp6:130254.Seq M00001449A:G10 36535 100.D11.sp6:131468.SeqM00001449C:D06 86110 RTA00000181AF.f.12.1 M00001449C:D06 8611080.E11.sp6:130266.Seq M00001450A:A02 39304RTA00000118A.j.21.1.Seq_THC151859 M00001450A:A02 39304RTA00000118A.j.21.1 M00001450A:A02 39304 79.F1.sp6:130076.SeqM00001450A:A02 39304 180.G9.sp6:135995.Seq M00001450A:A11 3266380.F11.sp6:130278.Seq M00001450A:A11 32663 RTA00000118A.1.8.1M00001450A:B12 82498 100.F11.sp6:131492.Seq M00001450A:B12 82498RTA00000118A.m.10.1 M00001450A:B12 82498 79.G1.sp6:130088.SeqM00001450A:D08 27250 80.G11.sp6:130290.Seq M00001450A:D08 27250180.B10.sp6:135936.Seq M00001450A:D08 27250 RTA00000181AF.g.10.1M00001452A:B04 84328 RTA00000118A.p.10.1 M00001452A:B04 8432879.A2.sp6:130017.Seq M00001452A:B12 86859 RTA00000118A.p.8.1M00001452A:B12 86859 79.B2.sp6:130029.Seq M00001452A:F05 85064RTA00000131A.m.23.1 M00001452A:F05 85064 79.D2.sp6:130053.SeqM00001452C:B06 16970 80.H11.sp6:130302.Seq M00001452C:B06 16970100.C12.sp6:131457.Seq M00001452C:B06 16970 RTA00000181AR.i.18.2M00001453A:E11 16130 80.A12.sp6:130219.Seq M00001453A:E11 16130100.D12.sp6:131469.Seq M00001453A:E11 16130 RTA00000119A.c.13.1M00001453C:F06 16653 80.B12.sp6:130231.Seq M00001453C:F06 16653RTA00000181AF.k.5.3 M00001454A:A09 83103 RTA00000119A.e.24.2M00001454A:A09 83103 79.G2.sp6:130089.Seq M00001454B:C12 7005121.D1.sp6:131917.Seq M00001454B:C12 7005 RTA00000181AF.k.24.1M00001454B:C12 7005 80.C12.sp6:130243.Seq M00001455B:E12 1307280.F12.sp6:130279.Seq M00001455B:E12 13072 RTA00000181AR.m.5.2M00001460A:F06 2448 89.A1.sp6:130667.Seq M00001460A:F06 2448RTA00000119A.j.21.1 M00001461A:D06 1531 89.C1.sp6:130691.SeqM00001461A:D06 1531 RTA00000119A.o.3.1 M00001465A:B11 1014579.F3.sp6:130078.Seq M00001465A:B11 10145 RTA00000120A.g.12.1M00001467A:B07 38759 89.F1.sp6:130727.Seq M00001467A:B07 38759RTA00000120A.m.12.3 M00001467A:D04 39508 RTA00000120A.o.2.1M00001467A:D04 39508 89.G1.sp6:130739.Seq M00001467A:E10 3944289.A2.sp6:130668.Seq M00001467A:E10 39442 RTA00000120A.o.21.1M00001468A:F05 7589 RTA00000120A.p.23.1 M00001468A:F05 758989.B2.sp6:130680.Seq M00001469A:A01 RTA00000121A.c.10.1 M00001469A:A0189.C2.sp6:130692.Seq M00001469A:C10 12081 89.D2.sp6:130704.SeqM00001469A:C10 12081 RTA00000133A.d.14.2 M00001469A:H12 1910589.E2.sp6:130716.Seq M00001469A:H12 19105 RTA00000133A.e.15.1M00001470A:C04 39425 89.G2.sp6:130740.Seq M00001470A:C04 39425RTA00000133A.f.1.1 M00001471A:B01 39478 89.H2.sp6:130752.SeqM00001471A:B01 39478 RTA00000133A.i.5.1 M00001487B:H06RTA00000182AF.1.15.1 M00001487B:H06 89.B3.sp6:130681.Seq M00001488B:F12RTA00000182AF.l.20.1 M00001488B:F12 89.C3.sp6:130693.Seq M00001494D:F067206 RTA00000182AF.o.15.1 M00001494D:F06 7206 89.E3.sp6:130717.SeqM00001499B:A11 10539 RTA00000183AF.a.24.1 M00001499B:A11 1053989.G3.sp6:130741.Seq M00001499B:A11 10539 173.B5.SP6:134085.SeqM00001500A:C05 5336 RTA00000183AF.b.13.1 M00001500A:C05 533689.H3.sp6:130753.Seq M00001504A:E01 RTA00000183AF.c.24.1 M00001504A:E0189.D4.sp6:130706.Seq M00001504A:E01 RTA00000183AF.c.24.1.Seq_THC125912M00001504C:A07 10185 RTA00000183AF.d.5.1 M00001504C:A07 1018589.E4.sp6:130718.Seq M00001505C:C05 89.H4.sp6:130754.Seq M00001505C:C05RTA00000183AF.e.1.1 M00001506D:A09 89.A5.sp6:130671.Seq M00001506D:A09RTA00000183AF.e.23.1 M00001506D:A09 121.G6.sp6:131958.Seq M00001507A:H0539168 RTA00000121A.l.10.1 M00001507A:H05 39168 89.B5.sp6:130683.SeqM00001535A:F10 39423 79.C5.sp6:130044.Seq M00001535A:F10 39423RTA00000134A.k.22.1 M00001541A:H03 39174 79.E5.sp6:130068.SeqM00001541A:H03 39174 RTA00000124A.n.13.1 M00001544A:G02 1982979.H5.sp6:130104.Seq M00001544A:G02 19829 RTA00000125A.h.24.4M00001545A:D08 13864 RTA00000125A.m.9.1 M00001545A:D08 1386479.B6.sp6:130033.Seq M00001551A:F05 39180 RTA00000126A.n.8.2M00001551A:F05 39180 79.A7.sp6:130022.Seq M00001552A:D11 39458RTA00000126A.p.15.2 M00001552A:D11 39458 79.D7.sp6:130058.SeqM00001557A:F03 39490 RTA00000128A.b.4.1 cDNA Library ES14 - ATCC# 207036Deposit Date - Dec. 22, 1998 M00001511A:H06 39412 RTA00000133A.k.17.1M00001511A:H06 39412 89.C5.sp6:130695.Seq M00001512A:A09 3918689.D5.sp6:130707.Seq M00001512A:A09 39186 RTA00000121A.p.15.1M00001512D:G09 3956 89.E5.sp6:130719.Seq M00001512D:G09 3956173.H5.SP6:134157.Seq M00001512D:G09 3956 RTA00000183AF.g.3.1M00001513B:G03 RTA00000183AF.g.9.1 M00001513B:G03 89.F5.sp6:130731.SeqM00001513B:G03 RTA00000183AF.g.9.1.Seq_THC198280 M00001513C:E08 14364RTA00000183AF.g.12.1 M00001513C:E08 14364 89.G5.sp6:130743.SeqM00001514C:D11 40044 RTA00000183AF.g.22.1 M00001514C:D11 40044RTA00000183AF.g.22.1.Seq_THC232899 M00001514C:D11 4004489.H5.sp6:130755.Seq M00001518C:B11 8952 89.A6.sp6:130672.SeqM00001518C:B11 8952 RTA00000183AF.h.15.1 M00001528B:H04 835889.D6.sp6:130708.Seq M00001528B:H04 8358 RTA00000183AF.i.5.1M00001531A:D01 38085 RTA00000123A.e.15.1 M00001531A:D01 3808589.E6.sp6:130720.Seq M00001534A:C04 16921 RTA00000183AF.k.6.1M00001534A:C04 16921 89.H6.sp6:130756.Seq M00001534A:D09 5097RTA00000134A.k.1.1 M00001534A:D09 5097 RTA00000134A.k.1.1.Seq_THC215869M00001534C:A01 4119 RTA00000183AF.k.16.1 M00001534C:A01 411989.C7.sp6:130697.Seq M00001535A:C06 20212 89.E7.sp6:130721.SeqM00001535A:C06 20212 RTA00000134A.1.22.1.Seq_THC128232 M00001535A:C0620212 RTA00000134A.1.22.1 M00001536A:B07 2696 RTA00000134A.m.13.1M00001536A:B07 2696 89.F7.sp6:130733.Seq M00001537A:F12 3942089.H7.sp6:130757.Seq M00001537A:F12 39420 RTA00000134A.o.23.1M00001540A:D06 8286 89.B8.sp6:130686.Seq M00001540A:D06 8286RTA00000183AF.o.1.1 M00001542A:E06 39453 89.E8.sp6:130722.SeqM00001542A:E06 39453 RTA00000135A.g.11.1 M00001544A:E06RTA00000184AF.a.8.1 M00001544A:E06 173.G7.SP6:134147.Seq M00001544A:E0689.H8.sp6:130758.Seq M00001545A:B02 89.B9.sp6:130687.Seq M00001545A:B02RTA00000135A.1.2.2 M00001548A:E10 5892 89.E9.sp6:130723.SeqM00001548A:E10 5892 RTA00000184AF.d.11.1 M00001548A:E10 5892RTA00000184AF.d.11.1.Seq_THC161896 M00001549C:E06 1634789.H9.sp6:130759.Seq M00001549C:E06 16347 RTA00000184AF.e.15.1M00001550A:A03 7239 89.A10.sp6:130676.Seq M00001550A:A03 7239RTA00000126A.m.4.2 M00001550A:G01 5175 RTA00000184AF.f.3.1M00001550A:G01 5175 89.B10.sp6:130688.Seq M00001551A:G06 22390RTA00000136A.j.13.1 M00001551A:G06 22390 89.C10.sp6:130700.SeqM00001551C:G09 3266 RTA00000184AR.g.1.1 M00001551C:G09 326689.D10.sp6:130712.Seq M00001553A:H06 8298 RTA00000127A.d.19.1M00001553A:H06 8298 89.G10.sp6:130748.Seq M00001553B:F12 457389.H10.sp6:130760.Seq M00001553B:F12 4573 RTA00000184AF.h.9.1M00001555A:B02 39539 RTA00000127A.i.21.1 M00001555A:B02 3953989.B11.sp6:130689.Seq M00001555A:C01 39195 89.C11.sp6:130701.SeqM00001555A:C01 39195 RTA00000137A.c.16.1 M00001555D:G10 4561RTA00000184AF.i.21.1 M00001555D:G10 4561 89.D11.sp6:130713.SeqM00001556A:C09 9244 89.E11.sp6:130725.Seq M00001556A:C09 9244RTA00000127A.l.3.1 M00001556B:G02 11294 RTA00000184AF.j.6.1M00001556B:G02 11294 89.A12.sp6:130678.Seq M00001557B:H10 5192173.E9.SP6:134125.Seq M00001557B:H10 5192 RTA00000184AF.k.2.1M00001557B:H10 5192 89.D12.sp6:130714.Seq M00001557D:D09 8761RTA00000184AF.k.12.1 M00001557D:D09 8761 89.E12.sp6:130726.SeqM00001558B:H11 7514 RTA00000184AF.k.21.1 M00001558B:H11 751489.G12.sp6:130750.Seq M00001559B:F01 89.H12.sp6:130762.SeqM00001559B:F01 RTA00000184AF.l.11.1 M00001560D:F10 655890.A1.sp6:130859.Seq M00001560D:F10 6558 RTA00000184AF.m.21.1M00001566B:D11 RTA00000184AF.p.3.1 M00001566B:D11 90.D1.sp6:130895.SeqM00001583D:A10 6293 RTA00000185AF.e.11.1 M00001583D:A10 629390.A2.sp6:130860.Seq M00001590B:F03 RTA00000185AF.g.11.1 M00001590B:F0390.C2.sp6:130884.Seq M00001597D:C05 10470 RTA00000185AF.k.6.1M00001597D:C05 10470 90.F2.sp6:130920.Seq M00001598A:G03 1699990.G2.sp6:130932.Seq M00001598A:G03 16999 RTA00000185AF.k.9.1M00001601A:D08 22794 RTA00000138A.b.5.1 M00001601A:D08 2279490.H2.sp6:130944.Seq M00001607A:E11 11465 RTA00000185AF.m.19.1M00001607A:E11 11465 90.A3.sp6:130861.Seq M00001608A:B03 7802RTA00000185AF.n.5.1 M00001608A:B03 7802 90.B3.sp6:130873.SeqM00001608B:E03 22155 RTA00000185AF.n.9.1 M00001608B:E03 2215590.C3.sp6:130885.Seq M00001608D:A11 RTA00000185AF.n.12.1 M00001608D:A1190.D3.sp6:130897.Seq M00001614C:F10 13157 RTA00000186AF.a.6.1M00001614C:F10 13157 90.E3.sp6:130909.Seq M00001617C:E02 17004RTA00000186AF.b.21.1 M00001617C:E02 17004 90.F3.sp6:130921.SeqM00001619C:F12 40314 90.G3.sp6:130933.Seq M00001619C:F12 40314RTA00000186AF.c.15.1 M00001621C:C08 40044 RTA00000186AF.d.1.1M00001621C:C08 40044 RTA00000186AF.d.1.1.Seq_THC232899 M00001621C:C0840044 90.H3.sp6:130945.Seq M00001621C:C08 40044 122.E1.sp6:132121.SeqM00001623D:F10 13913 RTA00000186AF.e.6.1 M00001623D:F10 1391390.A4.sp6:130862.Seq M00001632D:H07 RTA00000186AF.h.14.1.Seq_THC112525M00001632D:H07 RTA00000186AF.h.14.1 M00001632D:H07 90.E4.sp6:130910.SeqM00001632D:H07 176.A3.sp6:134514.Seq M00001644C:B07 39171RTA00000186AF.l.7.1 M00001644C:B07 39171 90.F4.sp6:130922.SeqM00001644C:B07 39171 217.A12.sp6:139369.Seq M00001645A:C12 19267RTA00000186AF.l.12.1.Seq_THC178183 M00001645A:C12 19267176.G3.sp6:134586.Seq M00001645A:C12 19267 RTA00000186AF.l.12.1M00001645A:C12 19267 90.G4.sp6:130934.Seq M00001648C:A01 466590.H4.sp6:130946.Seq M00001648C:A01 4665 RTA00000186AF.m.3.1M00001657D:C03 23201 RTA00000187AF.a.14.1 M00001657D:C03 2320190.B5.sp6:130875.Seq M00001657D:F08 76760 90.C5.sp6:130887.SeqM00001657D:F08 76760 RTA00000187AF.a.15.1 M00001662C:A09 23218RTA00000187AR.c.5.2 M00001662C:A09 23218 90.D5.sp6:130899.SeqM00001663A:E04 35702 90.E5.sp6:130911.Seq M00001663A:E04 35702RTA00000187AR.c.15.2 M00001669B:F02 6468 90.F5.sp6:130923.SeqM00001669B:F02 6468 RTA00000187AF.d.15.1 M00001670C:H02 1436790.G5.sp6:130935.Seq M00001670C:H02 14367 RTA00000187AF.e.8.1M00001673C:H02 7015 90.H5.sp6:130947.Seq M00001673C:H02 7015RTA00000187AF.f.18.1 M00001675A:C09 8773 RTA00000187AF.f.24.1M00001675A:C09 8773 90.A6.sp6:130864.Seq M00001675A:C09 8773RTA00000187AF.f.24.1.Seq_THC220002 M00001676B:F05 11460RTA00000187AF.g.12.1 M00001676B:F05 11460 90.B6.sp6:130876.SeqM00001676B:F05 11460 219.F2.sp6:139035.Seq M00001677D:A07 757090.D6.sp6:130900.Seq M00001677D:A07 7570 RTA00000187AF.g.24.1M00001677D:A07 7570 RTA00000187AF.g.24.1.Seq_THC168636 M00001678D:F124416 90.E6.sp6:130912.Seq M00001678D:F12 4416 RTA00000187AF.h.13.1M00001679A:F10 26875 RTA00000187AF.i.1.1 M00001679A:F10 2687590.A7.sp6:130865.Seq M00001679B:F01 6298 90.B7.sp6:130877.SeqM00001679B:F01 6298 RTA00000187AR.i.10.2 M00001680D:F08 1053990.F7.sp6:130925.Seq M00001680D:F08 10539 219.F6.sp6:139039.SeqM00001680D:F08 10539 RTA00000187AF.l.7.1 M00001682C:B12 1705590.G7.sp6:130937.Seq M00001682C:B12 17055 RTA00000187AF.m.3.1M00001682C:B12 17055 176.D6.sp6:134553.Seq M00001688C:F09 538290.A8.sp6:130866.Seq M00001688C:F09 5382 RTA00000187AF.m.23.2M00001693C:G01 4393 RTA00000187AF.n.17.1 M00001693C:G01 439390.B8.sp6:130878.Seq M00001716D:H05 67252 RTA00000187AF.o.6.1M00001716D:H05 67252 90.C8.sp6:130890.Seq M00003741D:C09 4010890.D8.sp6:130902.Seq M00003741D:C09 40108 RTA00000187AF.o.24.1M00003747D:C05 11476 RTA00000187AF.p.19.1 M00003747D:C05 1147690.E8.sp6:130914.Seq M00003747D:C05 11476RTA00000187AF.p.19.1.Seq_THC108482 M00003747D:C05 11476219.H8.sp6:139065.Seq M00003754C:E09 90.F8.sp6:130926.Seq M00003754C:E09RTA00000188AF.b.12.1 M00003761D:A09 RTA00000188AF.d.11.1 M00003761D:A0990.H8.sp6:130950.Seq M00003761D:A09 RTA00000188AF.d.11.1.Seq_THC212094M00003762C:B08 17076 RTA00000188AF.d.21.1.Seq_THC208760 M00003762C:B0817076 90.A9.sp6:130867.Seq M00003762C:B08 17076 RTA00000188AF.d.21.1M00003763A:F06 3108 RTA00000188AF.d.24.1 M00003763A:F06 310890.B9.sp6:130879.Seq M00003774C:A03 67907RTA00000188AF.g.11.1.Seq_THC123222 M00003774C:A03 67907RTA00000188AF.g.11.1 M00003774C:A03 67907 90.C9.sp6:130891.SeqM00003784D:D12 RTA00000188AF.i.8.1 M00003784D:D12 90.D9.sp6:130903.SeqM00003839A:D08 7798 RTA00000189AF.c.18.1 M00003839A:D08 779890.A10.sp6:130868.Seq M00003851B:D08 90.D10.sp6:130904.SeqM00003851B:D08 RTA00000189AF.f.7.1 M00003851B:D10 1359590.E10.sp6:130916.Seq M00003851B:D10 13595 RTA00000189AF.f.8.1M00003853A:D04 5619 90.F10.sp6:130928.Seq M00003853A:D04 5619RTA00000189AF.f.17.1 M00003853A:F12 10515 90.G10.sp6:130940.SeqM00003853A:F12 10515 RTA00000189AF.f.18.1 M00003856B:C02 462290.H10.sp6:130952.Seq M00003856B:C02 4622 RTA00000189AF.g.1.1M00003857A:H03 4718 90.B11.sp6:130881.Seq M00003857A:H03 4718RTA00000189AF.g.5.1.Seq_THC196102 M00003857A:H03 4718RTA00000189AF.g.5.1 cDNA Library ES15 - ATCC# 207037 Deposit Date - Dec.22, 1998 M00003867A:D10 90.C11.sp6:130893.Seq M00003867A:D10RTA00000189AF.h.17.1 M00003871C:E02 4573 RTA00000189AF.j.12.1M00003875C:G07 8479 90.G11.sp6:130941.Seq M00003875C:G07 8479RTA00000189AF.j.22.1 M00003875D:D11 90.H11.sp6:130953.Seq M00003875D:D11RTA00000189AF.j.23.1 M00003876D:E12 7798 90.A12.sp6:130870.SeqM00003876D:E12 7798 RTA00000189AF.k.12.1 M00003906C:E10 928590.H12.sp6:130954.Seq M00003906C:E10 9285 RTA00000190AF.d.7.1M00003907D:A09 39809 99.A1.sp6:131230.Seq M00003907D:A09 39809RTA00000190AF.e.3.1.Seq_THC150217 M00003907D:A09 39809RTA00000190AF.e.3.1 M00003907D:H04 16317 99.B1.sp6:131242.SeqM00003907D:H04 16317 RTA00000190AF.e.6.1 M00003909D:C03 8672RTA00000190AF.f.11.1 M00003909D:C03 8672 99.C1.sp6:131254.SeqM00003968B:F06 24488 RTA00000190AF.n.16.1 M00003968B:F06 2448899.C2.sp6:131255.Seq M00003970C:B09 40122 RTA00000190AF.n.23.1M00003970C:B09 40122 RTA00000190AF.n.23.1.Seq_THC109227 M00003970C:B0940122 99.D2.sp6:131267.Seq M00003974D:E07 23210 RTA00000190AF.o.20.1M00003974D:E07 23210 RTA00000190AF.o.20.1.Seq_THC207240 M00003974D:E0723210 99.E2.sp6:131279.Seq M00003974D:H02 23358RTA00000190AF.o.21.1.Seq_THC207240 M00003974D:H02 23358RTA00000190AF.o.21.1 M00003974D:H02 23358 99.F2.sp6:131291.SeqM00003981A:E10 3430 99.A3.sp6:131232.Seq M00003981A:E10 3430RTA00000191AF.a.9.1 M00003982C:C02 2433 RTA00000191AF.a.15.2M00003982C:C02 2433 99.B3.sp6:131244.Seq M00003982C:C02 2433RTA00000191AF.a.15.2.Seq_THC79498 M00004028D:C05 40073RTA00000191AF.e.3.1 M00004028D:C05 40073 99.E3.sp6:131280.SeqM00004035C:A07 37285 99.H3.sp6:131316.Seq M00004035C:A07 37285RTA00000191AF.f.11.1 M00004035D:B06 17036 RTA00000191AF.f.13.1M00004035D:B06 17036 99.A4.sp6:131233.Seq M00004072A:C03RTA00000191AF.j.9.1 M00004072A:C03 99.D4.sp6:131269.Seq M00004081C:D1015069 99.F4.sp6:131293.Seq M00004081C:D10 15069 RTA00000191AF.l.6.1M00004086D:G06 9285 99.H4.sp6:131317.Seq M00004086D:G06 9285RTA00000191AF.m.18.1 M00004105C:A04 7221 99.D5.sp6:131270.SeqM00004105C:A04 7221 RTA00000191AF.p.9.1 M00004171D:B03 4908RTA00000192AF.j.2.1 M00004171D:B03 4908 99.F6.sp6:131295.SeqM00004185C:C03 11443 RTA00000192AF.l.13.2 M00004185C:C03 11443123.A8.sp6:132272.Seq M00004185C:C03 11443 99.A7.sp6:131236.SeqM00004191D:B11 RTA00000192AF.m.12.1 M00004191D:B11 99.B7.sp6:131248.SeqM00004191D:B11 123.C8.sp6:132296.Seq M00004197D:H01 821099.C7.sp6:131260.Seq M00004197D:H01 8210 123.E8.sp6:132320.SeqM00004197D:H01 8210 RTA00000192AF.n.13.1 M00004203B:C12 1431199.D7.sp6:131272.Seq M00004203B:C12 14311 RTA00000192AF.o.2.1M00004214C:H05 11451 177.D8.sp6:134747.Seq M00004214C:H05 11451RTA00000192AF.p.17.1 M00004223D:E04 12971 RTA00000193AF.a.20.1M00004223D:E04 12971 99.B8.sp6:131249.Seq M00004269D:D06 490599.H8.sp6:131321.Seq M00004269D:D06 4905 RTA00000193AF.e.14.1M00004295D:F12 16921 99.D9.sp6:131274.Seq M00004295D:F12 16921RTA00000193AF.h.15.1 M00004296C:H07 13046 99.E9.sp6:131286.SeqM00004296C:H07 13046 RTA00000193AF.h.19.1 M00004307C:A06 9457RTA00000193AF.i.14.2 M00004307C:A06 9457 99.F9.sp6:131298.SeqM00004307C:A06 9457 123.D11.sp6:132311.Seq M00004312A:G03 26295RTA00000193AF.i.24.2 M00004312A:G03 26295 99.G9.sp6:131310.SeqM00004312A:G03 26295 RTA00000193AF.i.24.2.Seq_THC197345 M00004318C:D1021847 RTA00000193AF.j.9.1 M00004318C:D10 21847 99.H9.sp6:131322.SeqM00004359B:G02 RTA00000193AF.m.5.1.Seq_THC173318 M00004359B:G02RTA00000193AF.m.5.1 M00004505D:F08 RTA00000194AF.b.19.1 M00004505D:F0899.H10.sp6:131323.Seq M00004692A:H08 99.B11.sp6:131252.SeqM00004692A:H08 RTA00000194AF.c.24.1 M00004692A:H08 377.F4.sp6:141957.SeqM00005180C:G03 RTA00000194AF.f.4.1 cDNA Library ES16 - ATCC#207038Deposit Date - Dec. 22, 1998 M00001346D:E03 6806 RTA00000177AF.g.13.3M00001350A:B08 80.H2.sp6:130293.Seq M00001350A:B08 RTA00000177AF.i.6.2M00001357D:D11 4059 RTA00000177AF.n.18.3.Seq_THC123051 M00001357D:D114059 RTA00000177AF.n.18.3 M00001409C:D12 9577 RTA00000179AF.o.17.1M00001409C:D12 9577 80.E7.sp6:130262.Seq M00001418B:F03 9952RTA00000180AF.c.20.1 M00001418B:F03 9952RTA00000180AF.c.20.1.Seq_THC162284 M00001418B:F03 995280.E8.sp6:130263.Seq M00001418D:B06 8526 RTA00000180AF.d.1.1M00001421C:F01 9577 RTA00000180AF.d.23.1 M00001421C:F01 957780.G8.sp6:130287.Seq M00001429B:A11 4635 RTA00000180AF.i.20.1M00001432C:F06 RTA00000180AF.k.24.1 M00001439C:F08 40054RTA00000180AF.p.10.1 M00001442C:D07 16731 RTA00000181AF.a.20.1M00001442C:D07 16731 80.C10.sp6:130241.Seq M00001443B:F0180.D10.sp6:130253.Seq M00001443B:F01 RTA00000181AF.b.7.1 M00001445A:F0513532 80.E10.sp6:130265.Seq M00001445A:F05 13532 RTA00000181AF.c.4.1M00001446A:F05 7801 RTA00000181AF.c.21.1 M00001455A:E09 13238RTA00000181AF.m.4.1 M00001455A:E09 13238RTA00000181AF.m.4.1.Seq_THC140691 M00001460A:F12 39498RTA00000119A.j.20.1 M00001481D:A05 7985 RTA00000182AR.j.2.1M00001490B:C04 18699 RTA00000182AF.m.16.1 M00001490B:C04 1869989.D3.sp6:130705.Seq M00001500C:E04 9443 89.B4.sp6:130682.SeqM00001500C:E04 9443 RTA00000183AF.c.1.1 M00001532B:A06 399089.G6.sp6:130744.Seq M00001532B:A06 3990 RTA00000183AF.j.11.1M00001534A:F09 5321 89.B7.sp6:130685.Seq M00001534A:F09 5321RTA00000183AF.k.8.1 M00001535A:B01 7665 RTA00000134A.l.19.1M00001536A:C08 39392 89.G7.sp6:130745.Seq M00001536A:C08 39392RTA00000134A.m.16.1 M00001541A:F07 22085 RTA00000135A.e.5.2M00001542B:B01 RTA00000183AF.p.4.1 M00001542B:B01 89.F8.sp6:130734.SeqM00001544A:E03 12170 RTA00000125A.h.18.4 M00001545A:C03 19255RTA00000135A.m.18.1 M00001545A:C03 19255 184.B10.sp6:135547.SeqM00001545A:C03 19255 89.C9.sp6:130699.Seq M00001548A:H09 1058RTA00000126A.e.20.3.Seq_THC217534 M00001548A:H09 1058RTA00000126A.e.20.3 M00001548A:H09 1058 79.F6.sp6:130081.SeqM00001549A:B02 4015 RTA00000136A.e.12.1 M00001549A:B02 401579.G6.sp6:130093.Seq M00001549A:D08 10944 RTA00000126A.h.17.2M00001552B:D04 5708 RTA00000184AF.g.12.1 M00001552B:D04 570889.E10.sp6:130724.Seq M00001552D:A01 89.F10.sp6:130736.SeqM00001552D:A01 RTA00000184AF.g.22.1 M00001553D:D10 22814RTA00000184AF.h.14.1 M00001553D:D10 22814 89.A11.sp6:130677.SeqM00001558A:H05 RTA00000128A.c.20.1 M00001558A:H05 89.F12.sp6:130738.SeqM00001561A:C05 39486 RTA00000128A.m.22.2 M00001561A:C05 3948679.B8.sp6:130035.Seq M00001564A:B12 5053 RTA00000184AF.o.12.1M00001578B:E04 23001 RTA00000185AF.c.24.1 M00001579D:C03 653990.G1.sp6:130931.Seq M00001579D:C03 6539 173.A12.SP6:134080.SeqM00001579D:C03 6539 RTA00000185AF.d.11.1 M00001582D:F05RTA00000185AF.d.24.1 M00001587A:B11 39380 RTA00000129A.e.24.1M00001587A:B11 39380 79.E8.sp6:130071.Seq M00001604A:F05 39391RTA00000138A.c.3.1 M00001604A:F05 39391 79.A9.sp6:130024.SeqM00001624A:B06 3277 RTA00000138A.l.5.1 M00001624A:B06 3277217.E1.sp6:139406.Seq M00001624A:B06 3277 90.B4.sp6:130874.SeqM00001630B:H09 5214 90.D4.sp6:130898.Seq M00001630B:H09 5214122.C2.sp6:132098.Seq M00001630B:H09 5214 RTA00000186AF.g.11.1M00001651A:H01 RTA00000186AF.n.7.1 M00001651A:H01 90.A5.sp6:130863.SeqM00001677C:E10 14627 RTA00000187AF.g.23.1 M00001679C:F01 7809190.C7.sp6:130889.Seq M00001679C:F01 78091 RTA00000187AF.j.6.1M00001679C:F01 78091 176.G5.sp6:134588.Seq M00001686A:E06 4622RTA00000187AF.m.15.2 M00003796C:D05 5619RTA00000188AF.1.9.1.Seq_THC167845 M00003796C:D05 5619RTA00000188AF.1.9.1 M00003826B:A06 11350 RTA00000189AF.a.24.2M00003826B:A06 11350 90.F9.sp6:130927.Seq M00003833A:E05 21877RTA00000189AF.b.21.1 M00003837D:A01 7899 90.H9.sp6:130951.SeqM00003837D:A01 7899 RTA00000189AF.c.10.1 M00003846B:D06 6874RTA00000189AF.e.9.1 M00003846B:D06 6874 90.C10.sp6:130892.SeqM00003879B:D10 31587 RTA00000189AF.1.20.1 M00003879B:D10 3158790.C12.sp6:130894.Seq M00003879D:A02 14507 90.D12.sp6:130906.SeqM00003879D:A02 14507 RTA00000189AR.1.23.2 M00003891C:H0990.G12.sp6:130942.Seq M00003891C:H09 RTA00000189AF.p.8.1 M00003912B:D0112532 99.D1.sp6:131266.Seq M00003912B:D01 12532 RTA00000190AF.g.2.1M00004072B:B05 17036 RTA00000191AF.j.10.1 M00004081C:D12 14391RTA00000191AF.1.7.1 M00004111D:A08 6874 RTA00000192AF.a.14.1M00004111D:A08 6874 99.F5.sp6:131294.Seq M00004121B:G01177.H4.sp6:134791.Seq M00004121B:G01 99.H5.sp6:131318.Seq M00004121B:G01RTA00000192AF.c.2.1 M00004138B:H02 13272 99.A6.sp6:131235.SeqM00004138B:H02 13272 RTA00000192AF.e.3.1 M00004151D:B08 16977RTA00000192AF.g.3.1 M00004169C:C12 5319 99.E6.sp6:131283.SeqM00004169C:C12 5319 RTA00000192AF.i.12.1 M00004169C:C12 5319123.F7.sp6:132331.Seq M00004183C:D07 16392 RTA00000192AF.l.1.1M00004183C:D07 16392 RTA00000192AF.l.1.1.Seq_THC202071 M00004230B:C077212 RTA00000193AF.b.14.1 M00004230B:C07 7212 99.D8.sp6:131273.SeqM00004249D:F10 RTA00000193AF.c.21.1.Seq_THC222602 M00004249D:F10RTA00000193AF.c.21.1 M00004275C:C11 16914 99.A9.sp6:131238.SeqM00004275C:C11 16914 RTA00000193AF.f.5.1 M00004283B:A04 14286RTA00000193AF.f.22.1 M00004285B:E08 56020 RTA00000193AF.g.2.1M00004327B:H04 RTA00000193AF.j.20.1 M00004377C:F05 2102RTA00000193AF.n.7.1 M00004384C:D02 RTA00000193AF.n.15.1 M00004384C:D02RTA00000193AF.n.15.1.Seq_THC215687 M00004461A:B08 RTA00000194AR.a.10.2M00004461A:B09 RTA00000194AF.a.11.1 M00004691D:A05 RTA00000194AF.c.23.1M00004896A:C07 RTA00000194AF.d.13.1

The above material has been deposited with the American Type CultureCollection, Rockville, Md., under the accession number indicated. Thisdeposit will be maintained under the terms of the Budapest Treaty on theInternational Recognition of the Deposit of Microorganisms for purposesof Patent Procedure. The deposit will be maintained for a period of 30years following issuance of this patent, or for the enforceable life ofthe patent, whichever is greater. Upon issuance of the patent, thedeposit will be available to the public from the ATCC withoutrestriction.

This deposit is provided merely as convenience to those of skill in theart, and is not an admission that a deposit is required under 35 U.S.C.§112. The sequence of the polynucleotides contained within the depositedmaterial, as well as the amino acid sequence of the polypeptides encodedthereby, are incorporated herein by reference and are controlling in theevent of any conflict with the written description of sequences herein.A license may be required to make, use, or sell the deposited material,and no such license is granted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones

Where the ATCC deposit is composed of a pool of cDNA clones, the depositwas prepared by first transfecting each of the clones into separatebacterial cells. The clones were then deposited as a pool of equalmixtures in the composite deposit. Particular clones can be obtainedfrom the composite deposit using methods well known in the art. Forexample, a bacterial cell containing a particular clone can beidentified by isolating single colonies, and identifying coloniescontaining the specific clone through standard colony hybridizationtechniques, using an oligonucleotide probe or probes designed tospecifically hybridize to a sequence of the clone insert (e.g., a probebased upon unmasked sequence of the encoded polynucleotide having theindicated SEQ ID NO). The probe should be designed to have a T_(m) ofapproximately 80° C. (assuming 2° C. for each A or T and 4° C. for eachG or C). Positive colonies can then be picked, grown in culture, and therecombinant clone isolated. Alternatively, probes designed in thismanner can be used to PCR to isolate a nucleic acid molecule from thepooled clones according to methods well known in the art, e.g., bypurifying the cDNA from the deposited culture pool, and using the probesin PCR reactions to produce an amplified product having thecorresponding desired polynucleotide sequence.

Example 14 Source of Biological Materials and Overview of NovelPolynucleotides Expressed by the Biological Materials

Human colon cancer cell line Km12L4-A (Morika, W. A. K. et al., CancerResearch (1988) 48:6863) was used to construct a cDNA library from mRNAisolated from the cells. As described in the above overview, a total of4,693 sequences expressed by the Km12L4-A cell line were isolated andanalyzed; most sequences were about 275-300 nucleotides in length. TheKM12L4-A cell line is derived from the KM12C cell line. The KM12C cellline, which is poorly metastatic (low metastatic) was established inculture from a Dukes' stage B₂ surgical specimen (Morikawa et al. CancerRes. (1988) 48:6863). The KML4-A is a highly metastatic subline derivedfrom KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling etal. Proc. Ann. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12Cand KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) arewell-recognized in the art as a model cell line for the study of coloncancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. CancerRes. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin.Exp. Metastasis (1996) 14:246).

The sequences were first masked to eliminate low complexity sequencesusing the XBLAST masking program (Claverie “Effective Large-ScaleSequence Similarity Searches,” In: Computer Methods for MacromolecularSequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 AcademicPress, NY, N.Y. (1996); see particularly Claverie, in “Automated DNASequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993)17:191). Generally, masking does not influence the final search results,except to eliminate sequences of relative little interest due to theirlow complexity, and to eliminate multiple “hits” based on similarity torepetitive regions common to multiple sequences, e.g., Alu repeats.Masking resulted in the elimination of 43 sequences. The remainingsequences were then used in a BLASTN vs. Genbank search with searchparameters of greater than 70% overlap, 99% identity, and a p value ofless than 1×10⁻⁴⁰, which search resulted in the discarding of 1,432sequences. Sequences from this search also were discarded if theinclusive parameters were met, but the sequence was ribosomal orvector-derived.

The resulting sequences from the previous search were classified intothree groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP(non-redundant proteins) database search: (1) unknown (no hits in theGenbank search), (2) weak similarity (greater than 45% identity and pvalue of less than 1×10⁻⁵), and (3) high similarity (greater than 60%overlap, greater than 80% identity, and p value less than 1×10⁻⁵). Thissearch resulted in discard of 98 sequences as having greater than 70%overlap, greater than 99% identity, and p value of less than 1×10⁻⁴⁰.

The remaining sequences were classified as unknown (no hits), weaksimilarity, and high similarity (parameters as above). Two searches wereperformed on these sequences. First, a BLAST vs. EST database searchresulted in discard of 1771 sequences (sequences with greater than 99%overlap, greater than 99% similarity and a p value of less than 1×10⁻⁴⁰;sequences with a p value of less than 1×10⁻⁶⁵ when compared to adatabase sequence of human origin were also excluded). Second, a BLASTNvs. Patent GeneSeq database resulted in discard of 15 sequences (greaterthan 99% identity; p value less than 1×10⁻⁴⁰; greater than 99% overlap).

The remaining sequences were subjected to screening using other rulesand redundancies in the dataset. Sequences with a p value of less than1×10⁻¹¹¹ in relation to a database sequence of human origin werespecifically excluded. The final result provided the 2502 sequenceslisted in the accompanying Sequence Listing. The Sequence Listing isarranged beginning with sequences with no similarity to any sequence ina database searched, and ending with sequences with the greatestsimilarity. Each identified polynucleotide represents sequence from atleast a partial mRNA transcript. Polynucleotides that were determined tobe novel were assigned a sequence identification number.

The novel polynucleotides were assigned sequence identification numbersSEQ ID NOS:845-3346. The DNA sequences corresponding to the novelpolynucleotides are provided in the Sequence Listing. The majority ofthe sequences are presented in the Sequence Listing in the 5′ to 3′direction. A small number of sequences are listed in the SequenceListing in the 5′ to 3′ direction but the sequence as written isactually 3′ to 5′. These sequences are readily identified with thedesignation “AR” in the Sequence Name in Table 17 (inserted before theclaims). The sequences correctly listed in the 5′ to 3′ direction in theSequence Listing are designated “AF.” Table 17 provides: 1) the SEQ IDNO assigned to each sequence for use in the present specification; 2)the filing date of the U.S. priority application in which the sequencewas first filed; 3) the SEQ ID NO assigned to the sequence in thepriority application; 4) the sequence name used as an internalidentifier of the sequence; 5) the name assigned to the clone from whichthe sequence was isolated; and 6) the number of the cluster to which thesequence is assigned (Cluster ID; where the cluster ID is 0, thesequence was not assigned to any cluster

Because the provided polynucleotides represent partial mRNA transcripts,two or more polynucleotides of the invention may represent differentregions of the same mRNA transcript and the same gene. Thus, if two ormore SEQ ID NOS: are identified as belonging to the same clone, theneither sequence can be used to obtain the full-length mRNA or gene. Inaddition, some sequences are identified with multiple SEQ ID NOS, sincethese sequences were present in more than one filing. For example, SEQID NO:931 and SEQ ID NO:1844 represent the same sequence.

In order to confirm the sequences of SEQ ID NOS:845-3346, inserts of theclones corresponding to these polynucleotides were re-sequenced. These“validation” sequences are provided in SEQ ID NOS:3347-5106. Of thesevalidation sequences, SEQ ID NOS:3384, 4389, 4407, 5355, 5570, and 5593are not true validation sequences. Instead, SEQ ID NOS: 4389, 5355,5570, and 5593 represent “placeholder” sequences, i.e., sequences thatwere inserted into the Sequence Listing only to prevent renumbering ofthe subsequent sequences during generation of the Sequence Listing.Thus, reference to “SEQ ID NOS:845-6096,” “SEQ ID NOS:845-5950,” orother ranges of SEQ ID NOS that include these placeholder sequencesshould be read to exclude SEQ ID NOS: 4389, 5355, 5570, and 5593.

The validation sequences were often longer than the originalpolynucleotide sequences they validate, and thus often provideadditional sequence information. Validation sequences can be correlatedwith the original sequences they validate by referring to Table 17. Forexample, validation sequences of many SEQ ID NOS share the clone name ofthe sequence that they validate.

Example 15 Results of Public Database Search to Identify Function ofGene Products

SEQ ID NOS:845-3346, as well as the validation sequences were translatedin all three reading frames to determine the best alignment with theindividual sequences. These amino acid sequences and nucleotidesequences are referred, generally, as query sequences, which are alignedwith the individual sequences. Query and individual sequences werealigned using the BLAST programs, available over the world wide web siteof the NCBI. Again the sequences were masked to various extents toprevent searching of repetitive sequences or poly-A sequences, using theXBLAST program for masking low complexity as described above in Example1.

Table 18 (inserted before the claims) shows the results of thealignments. Table 18 refers to each sequence by its SEQ ID NO:, theaccession numbers and descriptions of nearest neighbors from the Genbankand Non-Redundant Protein searches, and the p values of the searchresults.

For each of “SEQ ID NOS:845-5950,” the best alignment to a protein orDNA sequence is included in Table 18. The activity of the polypeptideencoded by “SEQ ID NOS: 845-5950” is the same or similar to the nearestneighbor reported in Table 18. The accession number of the nearestneighbor is reported, providing a reference to the activities exhibitedby the nearest neighbor. The search program and database used for thealignment also are indicated as well as a calculation of the p value.

Full length sequences or fragments of the polynucleotide sequences ofthe nearest neighbors can be used as probes and primers to identify andisolate the full length sequence of “SEQ ID NOS: 845-5950.” The nearestneighbors can indicate a tissue or cell type to be used to construct alibrary for the full-length sequences of “SEQ ID NOS: 845-5950.”

“SEQ ID NOS: 845-5950” and the translations thereof may be humanhomologs of known genes of other species or novel allelic variants ofknown human genes. In such cases, these new human sequences are suitableas diagnostics or therapeutics. As diagnostics, the human sequences “SEQID NOS: 845-5950” exhibit greater specificity in detecting anddifferentiating human cell lines and types than homologs of otherspecies. The human polypeptides encoded by “SEQ ID NOS:845-5950” arelikely to be less immunogenic when administered to humans than homologsfrom other species. Further, on administration to humans, thepolypeptides encoded by “SEQ ID NOS: 845-5950” can show greaterspecificity or can be better regulated by other human proteins than arehomologs from other species.

Example 16 Members of Protein Families

The validation sequences (“SEQ ID NOS:3347-5950”) were used to conduct aprofile search as described in the specification above. Several of thepolynucleotides of the invention were found to encode polypeptideshaving characteristics of a polypeptide belonging to a known proteinfamilies (and thus represent new members of these protein families)and/or comprising a known functional domain (Table 19, inserted prior toclaims). Thus the invention encompasses fragments, fusions, and variantsof such polynucleotides that retain biological activity associated withthe protein family and/or functional domain identified herein.

Start and stop indicate the position within the individual sequencesthat align with the query sequence having the indicated SEQ ID NO. Thedirection (Dir) indicates the, orientation of the query sequence withrespect to the individual sequence, where forward (for) indicates thatthe alignment is in the same direction (left to right) as the sequenceprovided in the Sequence Listing and reverse (rev) indicates that thealignment is with a sequence complementary to the sequence provided inthe Sequence Listing.

Some polynucleotides exhibited multiple profile hits because, forexample, the particular sequence contains overlapping profile regions,and/or the sequence contains two different functional domains. Theseprofile hits are described in more detail below. The acronyms used inTable 19 are provided in parentheses following the full name of theprotein family or functional domain to which they refer. TABLE 19Polynucleotides encoding gene products of a protein family or having aknown functional domain(s). SEQ ID Biological NO: Validation SequenceActivity (Profile) Start Stop Score Direction 4764 393.E10.sp6:1489577tm_1 531 710 9520 for 3511 172.F10.sp6:133946 7tm_2 45 724 8708 rev3602 177.C6.sp6:134733 7tm_2 41 697 9828 rev 3777 184.C7.sp6:1355567tm_2 3 834 8987 for 3973 121.E12.sp6:131940 7tm_2 245 1324 9550 rev4209 172.A7.sp6:133883 7tm_2 94 761 8743 rev 4262 123.F9.sp6:1323337tm_2 203 585 8785 rev 4263 123.F9.sp6:132333 7tm_2 203 585 8785 rev4441 394.G2.sp6:149165 7tm_2 73 793 9209 for 4492 370.C5.sp6:1417267tm_2 76 770 9269 for 4530 370.B1.sp6:141710 7tm_2 89 662 8791 for 4539368.A12.sp6:141322 7tm_2 121 719 9015 rev 4540 368.A12.sp6:141322 7tm_2121 719 9015 rev 5016 219.C10.sp6:139007 7tm_2 46 774 11394 rev 5060368.D11.sp6:141357 7tm_2 66 775 9384 rev 5072 368.A11.sp6:141321 7tm_2 71079 9097 for 5285 99.F7.sp6:131296 7tm_2 534 1265 10956 rev 528699.F7.sp6:131296 7tm_2 534 1265 10956 rev 5326 100.D2.sp6:131459 7tm_2122 1404 9296 rev 5339 395.B12.sp6:149307 7tm_2 79 1432 10427 rev 536990.B4.sp6:130874 7tm_2 4 691 9435 for 5460 100.D5.sp6:131462 7tm_2 6551349 9255 for 5497 100.D7.sp6:131464 7tm_2 357 1346 11461 rev 5498100.D7.sp6:131464 7tm_2 357 1346 11461 rev 5502 100.H6.sp6:131511 7tm_2119 1035 10001 rev 5503 100.G6.sp6:131499 7tm_2 363 1188 9901 rev 5504100.F6.sp6:131487 7tm_2 50 1127 8799 for 5505 100.F6.sp6:131487 7tm_2 501127 8799 for 5554 367.H9.sp6:141210 7tm_2 143 1266 11883 rev 5599370.F4.sp6:141761 7tm_2 78 704 8942 for 5700 367.H11.sp6:141212 7tm_2176 1227 9975 rev 5729 123.E10.sp6:132322 7tm_2 210 691 9071 rev 5744123.E10.sp6:132322 7tm_2 210 691 9071 rev 5745 123.E10.sp6:132322 7tm_2210 691 9071 rev 3500 176.H11.sp6:134606 ANK 207 290 4450 for 3399180.C9.sp6:135947 asp 156 670 6710 for 4476 368.H11.sp6:141405 asp 1361226 6880 rev 5049 368.B5.sp6:141327 asp 309 806 6073 for 5095369.D6.sp6:141546 asp 434 1332 6263 rev 5097 396.F9.sp6:149544 asp 971106 5999 rev 5105 216.G10.sp6:139247 asp 74 703 6188 rev 5209122.H12.sp6:132168 asp 152 1040 6183 rev 5342 80.H6.sp6:130297 asp 61418 5944 rev 5508 172.E5.sp6:133929 asp 219 976 6434 for 5562185.D9.sp6:135762 asp 31 872 5944 rev 5577 185.D9.sp6:135762 asp 31 8725944 rev 5590 176.B10.sp6:134533 asp 253 1446 6079 rev 5666177.F3.sp6:134766 asp 0 894 6336 rev 5698 184.F11.sp6:135596 asp 61 7376416 rev 5700 367.H11.sp6:141212 asp 81 1187 6182 rev 5773180.E6.sp6:135968 asp 81 706 6150 for 5775 180.E6.sp6:135968 asp 81 7066150 for 3567 180.F2.sp6:135976 ATPases 135 627 11664 for 3686217.H11.sp6:139452 ATPases 2 701 5972 for 3863 216.B1.sp6:139178 ATPases170 616 6150 for 3890 121.B8.sp6:131900 ATPases 13 635 5867 rev 403480.D2.sp6:130245 ATPases 13 386 6068 for 4134 176.C6.sp6:134541 ATPases85 579 5883 for 4514 369.C10.sp6:141538 ATPases 329 730 6206 for 4842394.H8.sp6:149183 ATPases 21 571 5954 rev 4963 218.F11.sp6:138852ATPases 313 816 6057 for 5003 219.A7.sp6:138980 ATPases 88 662 6145 for5067 368.F9.sp6:141379 ATPases 178 648 5937 for 5228 181.G11.sp6:135354ATPases 362 769 5900 rev 5317 369.B4.sp6:141520 ATPases 4 412 14130 for5384 218.C8.sp6:138813 ATPases 12 576 5782 rev 5404 404.G6.sp6:162933ATPases 86 605 6001 rev 5533 367.H8.sp6:141209 ATPases 17 476 5905 rev5629 184.E5.sp6:135578 ATPases 184 632 5943 for 5636 184.C6.sp6:135555ATPases 333 813 5773 for 5691 184.B11.sp6:135548 ATPases 14 498 6140 for5885 377.C1.sp6:141918 ATPases 4 655 5933 for 4248 176.F10.sp6:134581Bcl-2 69 356 16419 for 4880 367.F5.sp6:141182 bromodomain 40 210 8810for 5333 369.D3.sp6:141543 bromodomain 63 230 10270 for 4252172.E1.sp6:133925 BZIP 146 298 4066 for 4795 393.G5.sp6:148976 BZIP 116304 5931 for 5694 172.E9.sp6:133933 BZIP 91 260 4366 for 4462370.B12.sp6:141721 cyclin 118 324 8980 for 4739 395.G6.sp6:149361 cyclin11 281 6930 for 5380 395.G8.sp6:149363 cyclin 12 279 5950 for 529999.F5.sp6:131294 Cys-protease 72 348 18479 for 5528 180.D1.sp6:135951Cys-protease 38 992 10103 rev 5532 180.D1.sp6:135951 Cys-protease 38 99210103 rev 5645 177.E4.sp6:134755 Cys-protease 48 326 19999 for 5503100.G6.sp6:131499 DAG_PE_bind 605 702 6290 rev 5665 377.C8.sp6:141925Dead_box_helic 172 828 7867 rev 5927 216.A1.sp6:139166 Dead_box_helic 44589 26532 for 3578 177.G4.sp6:134779 EFhand 79 153 3780 for 3737185.A1.sp6:135718 EFhand 287 358 2580 rev 4619 377.A5.sp6:141898 EFhand477 563 3010 for 4900 367.B7.sp6:141136 EFhand 225 272 2500 rev 4996218.B10.sp6:138803 EFhand 40 114 2640 rev 4997 218.B10.sp6:138803 EFhand40 114 2640 rev 4998 218.C10.sp6:138815 EFhand 39 113 2640 rev 5749393.H12.sp6:148995 EFhand 145 231 4640 for 5787 219.A9.sp6:138982 EFhand685 750 2550 rev 3693 218.B5.sp6:138798 Ets_Nterm 340 531 10400 for 3572180.A2.sp6:135916 FNtypeII 291 423 6400 rev 3862 216.C1.sp6:139190FNtypeII 501 634 6460 for 5340 218.G1.sp6:138854 FNtypeII 20 141 6180rev 5758 393.H8.sp6:148991 FNtypeII 448 576 6110 for 3348181.C3.sp6:135298 G-alpha 66 715 8084 rev 4134 176.C6.sp6:134541 G-alpha62 690 9062 for 5132 121.B4.sp6:131896 G-alpha 46 447 21415 for 5288217.D12.sp6:139405 G-alpha 15 702 40404 for 5406 404.B7.sp6:162874G-alpha 120 682 8424 for 3347 180.A11.sp6:135925 helicase_C 165 479 4494for 5313 369.C4.sp6:141532 helicase_C 559 756 3732 rev 5864185.D12.sp6:135765 helicase_C 381 534 5000 for 5085 396.H8.sp6:149567homeobox 80 230 5170 for 3394 180.E5.sp6:135967 mkk 342 612 5791 for4251 172.F1.sp6:133937 mkk 94 669 5688 rev 4295 123.A2.sp6:132266 mkk 26378 7889 for 4444 394.B3.sp6:149106 mkk 32 782 9544 for 4490370.H4.sp6:141785 mkk 18 307 9394 for 4524 369.G11.sp6:141587 mkk 182725 5375 for 5019 219.H10.sp6:139067 mkk 280 723 15454 for 5049368.B5.sp6:141327 mkk 249 725 5502 for 5122 181.C9.sp6:135304 mkk 168880 5551 rev 5166 121.F6.sp6:131946 mkk 111 730 5399 for 5621177.E2.sp6:134753 mkk 288 636 5720 rev 5326 100.D2.sp6:131459 PDEase 8491195 5945 for 3422 181.H11.sp6:135366 protkinase 116 710 5531 for 3556177.G7.sp6:134782 protkinase 6 511 5445 for 3679 218.C1.sp6:138806protkinase 127 747 5492 for 3687 218.E1.sp6:138830 protkinase 64 7265592 rev 3815 217.F4.sp6:139421 protkinase 83 702 5818 rev 3853217.A4.sp6:139361 protkinase 57 682 5395 rev 3928 121.E2.sp6:131930protkinase 69 658 5593 rev 4070 100.D8.sp6:131465 protkinase 174 6205453 for 4118 100.C3.sp6:131448 protkinase 228 736 5616 for 4200172.B5.sp6:133893 protkinase 148 715 5381 for 4221 172.B6.sp6:133894protkinase 119 775 5616 for 4295 123.A2.sp6:132266 protkinase 24 3849797 for 4444 394.B3.sp6:149106 protkinase 357 780 11395 for 4479377.G11.sp6:141976 protkinase 117 739 5992 for 4490 370.H4.sp6:141785protkinase 24 275 8338 for 4509 370.F2.sp6:141759 protkinase 33 800 5658for 4513 369.B10.sp6:141526 protkinase 1 482 5504 rev 4544369.D2.sp6:141542 protkinase 28 661 5428 for 4554 369.G6.sp6:141582protkinase 71 631 5751 for 4635 396.C11.sp6:149510 protkinase 27 7095793 rev 4749 393.H7.sp6:148990 protkinase 88 680 5470 rev 4763393.D10.sp6:148945 protkinase 72 594 5617 for 4888 367.G4.sp6:141193protkinase 30 699 5439 for 4916 368.B2.sp6:141324 protkinase 44 800 5556for 4961 218.D11.sp6:138828 protkinase 38 781 6423 for 5019219.H10.sp6:139067 protkinase 277 717 15720 for 5217 216.E5.sp6:139218protkinase 115 710 5537 for 5413 100.C10.sp6:131455 protkinase 56 7835556 rev 5599 370.F4.sp6:141761 protkinase 39 803 5635 for 5604370.F3.sp6:141760 protkinase 188 775 5771 for 5651 184.H3.sp6:135612protkinase 23 699 5515 for 5903 180.B5.sp6:135931 protkinase 182 6715718 rev 5946 393.F4.sp6:148963 protkinase 28 650 5345 for 4515369.D10.sp6:141550 ras 12 332 9802 for 4780 393.A3.sp6:148902 Thioredox0 263 5887 rev 4771 393.F11.sp6:148970 TNFR_c6 151 261 6445 for 3800184.E10.sp6:135583 transmembrane4 19 483 8339 rev 3825 217.E6.sp6:139411transmembrane4 83 728 8417 for 4680 396.C9.sp6:149508 transmembrane4 300924 9444 rev 4882 367.A6.sp6:141123 transmembrane4 32 495 8407 rev 5208123.A1.sp6:132265 transmembrane4 1289 1548 8114 rev 5250122.C1.sp6:132097 transmembrane4 6 535 8122 for 5275 122.E4.sp6:132124transmembrane4 10 530 8829 for 5285 99.F7.sp6:131296 transmembrane4 6131253 9443 rev 5286 99.F7.sp6:131296 transmembrane4 613 1253 9443 rev5497 100.D7.sp6:131464 transmembrane4 335 1207 8255 rev 5498100.D7.sp6:131464 transmembrane4 335 1207 8255 rev 5554367.H9.sp6:141210 transmembrane4 398 1130 8352 rev 5788180.H7.sp6:136005 transmembrane4 356 983 8356 rev 4225 176.D9.sp6:134556trypsin 164 764 9670 rev 5528 180.D1.sp6:135951 trypsin 371 1229 10479rev 5532 180.D1.sp6:135951 trypsin 371 1229 10479 rev 3598177.H6.sp6:134793 WD_domain 345 437 6510 for 3890 121.B8.sp6:131900WD_domain 98 193 6400 for 4071 100.B10.sp6:131443 WD_domain 544 642 6590for 5087 121.A8.sp6:131888 WD_domain 93 188 6400 for 5890185.F10.sp6:135787 WD_domain 382 480 5880 for 3973 121.E12.sp6:131940Wnt_dev_sign 101 821 12160 rev 4017 99.G6.sp6:131307 Wnt_dev_sign 49 88012334 rev 4234 176.C9.sp6:134544 Wnt_dev_sign 249 854 11038 rev 4235176.C9.sp6:134544 Wnt_dev_sign 249 854 11038 rev 4500 370.G6.sp6:141775Wnt_dev_sign 211 785 11490 rev 4680 396.C9.sp6:149508 Wnt_dev_sign 2821017 12318 rev 5097 396.F9.sp6:149544 Wnt_dev_sign 482 1298 11217 rev5174 122.A2.sp6:132074 Wnt_dev_sign 94 933 12383 rev 5203123.B2.sp6:132278 Wnt_dev_sign 538 1435 11785 for 5208 123.A1.sp6:132265Wnt_dev_sign 760 1544 12660 rev 5219 122.G10.sp6:132154 Wnt_dev_sign 29884 11603 rev 5229 122.A2.sp6:132074 Wnt_dev_sign 94 933 12383 rev 5253121.F12.sp6:131952 Wnt_dev_sign 9 734 11167 rev 5285 99.F7.sp6:131296Wnt_dev_sign 560 1399 13749 rev 5286 99.F7.sp6:131296 Wnt_dev_sign 5601399 13749 rev 5379 395.F10.sp6:149353 Wnt_dev_sign 100 907 11535 rev5430 123.A4.sp6:132268 Wnt_dev_sign 80 1122 11249 rev 5449404.D5.sp6:162896 Wnt_dev_sign 31 816 11304 rev 5497 100.D7.sp6:131464Wnt_dev_sign 467 1314 11882 rev 5498 100.D7.sp6:131464 Wnt_dev_sign 4671314 11882 rev 5509 177.B11.sp6:134726 Wnt_dev_sign 137 1266 12708 rev5512 177.B11.sp6:134726 Wnt_dev_sign 137 1266 12708 rev 5526177.B11.sp6:134726 Wnt_dev_sign 137 1266 12708 rev 5554367.H9.sp6:141210 Wnt_dev_sign 692 1481 12886 rev 5562 185.D9.sp6:135762Wnt_dev_sign 129 890 11145 rev 5568 377.D2.sp6:141931 Wnt_dev_sign 4001227 11044 rev 5577 185.D9.sp6:135762 Wnt_dev_sign 129 890 11145 rev5700 367.H11.sp6:141212 Wnt_dev_sign 295 1669 13366 rev 5710377.D4.sp6:141933 Wnt_dev_sign 549 1380 14522 rev 5769219.B12.sp6:138997 Wnt_dev_sign 312 1214 13188 rev 5803219.B12.sp6:138997 Wnt_dev_sign 312 1214 13188 rev 4253172.D1.sp6:133913 Y_phosphatase 476 804 6932 for 4262 123.F9.sp6:132333Y_phosphatase 28 439 6096 rev 4263 123.F9.sp6:132333 Y_phosphatase 28439 6096 rev 4501 370.H6.sp6:141787 Y_phosphatase 148 554 6481 for 4648404.B10.sp6:162877 Y_phosphatase 104 466 6446 rev 4650404.D10.sp6:162901 Y_phosphatase 9 614 6516 for 4818 395.F2.sp6:149345Y_phosphatase 164 645 6093 rev 5082 121.E9.sp6:131937 Y_phosphatase 240777 6147 rev 5107 216.F10.sp6:139235 Y_phosphatase 21 504 6342 for 5187122.E9.sp6:132129 Y_phosphatase 381 807 6036 rev 5207 123.B1.sp6:132277Y_phosphatase 61 510 6229 rev 5278 219.F4.sp6:139037 Y_phosphatase 2 26110353 for 5317 369.B4.sp6:141520 Y_phosphatase 231 768 6110 rev 5473404.E11.sp6:162914 Y_phosphatase 580 920 6005 rev 5938 217.A3.sp6:139360Y_phosphatase 263 622 6222 rev 3582 177.A6.sp6:134709 Zincfing_C2H2 65127 4380 for 3604 177.A6.sp6:134709 Zincfing_C2H2 65 127 4380 for 3676218.B2.sp6:138795 Zincfing_C2H2 94 156 4940 for 4580 377.H8.sp6:141985Zincfing_C2H2 495 557 4850 for 4606 377.G2.sp6:141967 Zincfing_C2H2 52114 4380 for 4607 377.G2.sp6:141967 Zincfing_C2H2 52 114 4380 for 5638377.G4.sp6:141969 Zincfing_C2H2 247 308 3930 for 5934 185.C4.sp6:135745Zincfing_C2H2 238 300 4540 for 4618 377.E4.sp6:141945 Zincfing_C3HC4 128244 9335 for 5321 181.E3.sp6:135322 Zincfing_C3HC4 321 445 8221 for

a) Seven Transmembrane Integral Membrane Proteins—Rhodopsin Family(7tm_(—)1). Several of the validation sequences, and thus theircorresponding sequence within SEQ ID NOS:845-3346, correspond to asequence encoding a polypeptide that is a member of the seventransmembrane receptor rhodopsin family. G-protein coupled receptors ofthe seven transmembrane rhodopsin family (also called R7G) are anextensive group of hormones, neurotransmitters, and light receptorswhich transduce extracellular signals by interaction with guaninenucleotide-binding (G) proteins (Strosberg A. D. Eur. J. Biochem. (1991)196:1, Kerlavage A. R. Curr. Opin. Struct. Biol. (1991) 1:394, Probst,et al., DNA Cell Biol. (1992) 11:1, Savarese, et al., Biochem. J. (1992)283:1. The receptors that are currently known to belong to this familyare: 1) 5-hydroxytryptamine (serotonin) 1A to 1F, 2A to 2C, 4, 5A, 5B, 6and 7 (Branchek T., Curr. Biol. (1993) 3:315); 2) acetylcholine,muscarinic-type, M1 to M5; 3) adenosine A1, A2A, A2B and A3 (Stiles G.L. J. Biol. Chem. (1992) 267:6451; 4) adrenergic alpha-1A to -1C;alpha-2A to -2D; beta-1 to -3 (Friell T. et al., Trends Neurosci. (1988)11:321); 5) angiotensin II types I and II; 6) bombesin subtypes 3 and 4;7) bradykinin B1 and B2; 8) c3a and C5a anaphylatoxin; 9) cannabinoidCB1 and CB2; 10) chemokines C-C CC-CKR-1 to CC-CKR-8; 11) ChemokinesC-X-C CXC-CKR-1 to CXC-CKR-4; 12) Cholecystokinin-A andcholecystokinin-B/gastrin Dopamine D1 to D5 (Stevens C. F., Curr. Biol.(1991) 1:20); 13) Endothelin ET-a and ET-b (Sakurai T. et al., TrendsPharmacol. Sci. (1992) 13:103-107); 14) fMet-Leu-Phe (fMLP) (Nformylpeptide); 15) Follicle stimulating hormone (FSH-R); 16) Galanin; 17)Gastrin-releasing peptide (GRP-R); 18) Gonadotropin-releasing hormone(GNRH-R); 19) Histamine H1 and H2 (gastric receptor I); 20)Lutropin-choriogonadotropic hormone (LSH-R) (Salesse R., et al.,Biochimie (1991) 73:109); 21) Melanocortin MC1R to MC5R; 22) Melatonin;23) Neuromedin B (NMB-R); 24) Neuromedin K (NK-3R); 25) Neuropeptide Ytypes 1 to 6; 26) Neurotensin (NT-R); 27) Octopamine (tyramine), frominsects; 28) Odorants (Lancet D., et al., Curr. Biol. (1993)3:668; 29)Opioids delta-, kappa- and mu-types (Uhl G. R., et al., Trends Neurosci.(1994) 17:89; 30) Oxytocin (OT-R); 31) Platelet activating factor(PAF-R); 32) Prostacyclin; 33) Prostaglandin D2; 34) Prostaglandin E2,EP1 to EP4 subtypes; 35) Prostaglandin F2; 36) Purinoreceptors (ATP)(Barnard E. A., et al., Trends Pharmacol. Sci. (1994)15:67; 37);Somatostatin types 1 to 5; 38) Substance-K (NK-2R); Substance-P (NK-1R);39) Thrombin; 40) Thromboxane A2; 41) Thyrotropin (TSH-R) (Salesse R.,et al., Biochimie (1991) 73:109); 42) Thyrotropin releasing factor(TRH-R); 42) Vasopressin V1a, V1b and V2; 43) Visual pigments (opsinsand rhodopsin) (Applebury M. L., et al., Vision Res. (1986) 26:1881; 44)Proto-oncogene mas; 45) A number of orphan receptors (whose ligand isnot known) from mammals and birds; 46) Caenorhabditis elegans putativereceptors C06G4.5, C38C10.1, C43C3.2; 47) T27D1.3 and ZC84.4; 48) Threeputative receptors encoded in the genome of cytomegalovirus: US27, US28,and UL33; and 49) ECRF3, a putative receptor encoded in the genome ofherpesvirus saimiri.

The structure of these receptors is thought to be identical. They haveseven hydrophobic regions, each of which most probably spans themembrane. The N-terminus is located on the extracellular side of themembrane and is often glycosylated, while the C-terminus is cytoplasmicand generally phosphorylated. Three extracellular loops alternate withthree intracellular loops to link the seven transmembrane regions. Most,but not all of these receptors, lack a signal peptide. The mostconserved parts of these proteins are the transmembrane regions and thefirst two cytoplasmic loops. A conserved acidic-Arg-aromatic triplet ispresent in the N-terminal extremity of the second cytoplasmic loop(Attwood T. K., Eliopoulos E. E., Findlay J. B. C. Gene (1991)98:153-159) and could be implicated in the interaction with G proteins.

b) Seven Transmembrane Integral Membrane Proteins—Secretin Family(7tm_(—)2). Several of the validation sequences, and thus theircorresponding sequence in the sequence listing, correspond to a sequenceencoding a polypeptide that is a member of the seven transmembranereceptor secretin family. A number of peptide hormones bind to G-proteincoupled receptors that, while structurally similar to the majority ofG-protein coupled receptors (R7G) (see profile for 7 transmembranereceptors (rhodopsin family), do not show any similarity at the level oftheir sequence, thus new family whose current known members (Jueppner etal. Science (1991) 254:1024; Hamann et al. Genomnics (1996) 32:144)are: 1) calcitonin receptor, 2) calcitonin gene-related peptidereceptor; 3) corticotropin releasing factor receptor types 1 and 2; 4)gastric inhibitory polypeptide receptor; 5) glucagon receptor; 6)glucagon-like peptide 1 receptor; 7) growth hormone-releasing hormonereceptor; 7) parathyroid hormone/parathyroid hormone-related peptidetypes 1 and 2; 8) pituitary adenylate cyclase activating polypeptidereceptor; 9) secretin receptor; 10) vasoactive intestinal peptidereceptor types 1 and 2; 10) insects diuretic hormone receptor; 11)Caenorhabditis elegans putative receptor C13B9.4; 12) Caenorhabditiselegans putative receptor ZK643.3; 13) human leucocyte CD97 (whichcontains 3 EGF-like domains in its N-terminal section); 14) human cellsurface glycoprotein EMR1 (which contains 6 EGF-like domains in itN-terminal section); and 15) mouse cell surface glycoprotein F4/80(which contains 7 EGF-like domains in its N-terminal section). All of 1)through 10) are coupled to G-proteins which activate both adenylylcyclase and the phosphatidylinositol-calcium pathway.

Like classical R7G the secretin family of 7 transmembrane proteinscontain seven transmembrane regions. Their N-terminus is located on theextracellular side of the membrane and potentially glycosylated, whiletheir C-terminus is cytoplasmic. But apart from these topologicalsimilarities they do not share any region of sequence similarity and aretherefore probably not evolutionary related.

Every receptor in the 7 transmember secretin family is encoded onmultiple exons, and several of these functionally distinct products. TheN-terminal extracellular domain of these receptors contains fiveconserved cysteines residues that may be involved in disulfide bonds,with a consensus pattern in the region that spans the first threecysteines. One of the most highly conserved regions spans the C-terminalpart of the last transmembrane region and the beginning of the adjacentintracellular region. This second region is used as a second signaturepattern.

c) Ank Repeats (ANK). The ankyrin motif is a 33 amino acid sequencenamed after the protein ankyrin which has 24 tandem 33-amino-acidmotifs. Ank repeats were originally identified in the cell-cycle-controlprotein cdc10 (Breeden et al., Nature (1987) 329:651). Proteinscontaining ankyrin repeats include ankyrin, myotropin, I-kappaBproteins, cell cycle protein cdc10, the Notch receptor (Matsuno et al.,Development (1997) 124(21):4265); G9a (or BAT8) of the class III regionof the major histocompatibility complex (Biochem J. 290:811-818, 1993),FABP, GABP, 53BP2, Lin12, glp-1, SW14, and SW16. The functions of theankyrin repeats are compatible with a role in protein-proteininteractions (Bork, Proteins (1993) 17(4):363; Lambert and Bennet, Eur.J. Biochem. (1993) 211:1; Kerr et al., Current Op. Cell Biol. (1992)4:496; Bennet et al., J. Biol. Chem. (1980) 255:6424).

The 90 kD N-terminal domain of ankyrin contains a series of 2433-amino-acid ank repeats. (Lux et al., Nature (1990) 344:36-42, Lambertet al., PNAS USA (1990) 87:1730.) The 24 ank repeats form four foldedsubdomains of 6 repeats each. These four repeat subdomains mediateinteractions with at least 7 different families of membrane proteins.Ankyrin contains two separate binding sites for anion exchanger dimers.One site utilizes repeat subdomain two (repeats 7-12) and the otherrequires both repeat subdomains 3 and 4 (repeats 13-24). Since the anionexchangers exist in dimers, ankyrin binds 4 anion exchangers at the sametime (Michaely and Bennett, J. Biol. Chem. (1995) 270(37):22050). Therepeat motifs are involved in ankyrin interaction with tubulin,spectrin, and other membrane proteins. (Lux et al., Nature (1990)344:36.)

The Rel/NF-kappaB/Dorsal family of transcription factors have activitythat is controlled by sequestration in the cytoplasm in association withinhibitory proteins referred to as I-kappaB. (Gilmore, Cell (1990)62:841; Nolan and Baltimore, Curr Opin Genet Dev. (1992) 2:211;Baeuerle, Biochim Biophys Acta (1991)1072:63; Schmitz et al., TrendsCell Biol. (1991) 1:130.) I-kappaB proteins contain 5 to 8 copies of 33amino acid ankyrin repeats and certain NF-kappaB/rel proteins are alsoregulated by cis-acting ankyrin repeat containing domains includingp105NF-kappaB which contains a series of ankyrin repeats (Diehl andHannink, J. Virol. (1993) 67(12):7161). The I-kappaBs and Cactus (alsocontaining ankyrin repeats) inhibit activators through differentialinteractions with the Rel-homology domain. The gene family includesproto-oncogenes, thus broadly implicating I-kappaB in the control ofboth normal gene expression and the aberrant gene expression that makescells cancerous. (Nolan and Baltimore, Curr Opin Genet Dev. (1992)2(2):211-220). In the case of rel/NF-kappaB and pp40/I-kappaB(, both theankyrin repeats and the carboxy-terminal domain are required forinhibiting DNA-binding activity and direct association of pp40/I-kappaB(with rel/NF-kappaB protein. The ankyrin repeats and the carboxy-terminalof pp40/I-kappaB( form a structure that associates with the rel homologydomain to inhibit DNA binding activity (Inoue et al., PNAS USA (1992)89:4333).

The 4 ankyrin repeats in the amino terminus of the transcription factorsubunit GABP□ are required for its interaction with the GABP□ subunit toform a functional high affinity DNA-binding protein. These repeats canbe crosslinked to DNA when GABP is bound to its target sequence.(Thompson et al., Science (1991) 253:762; LaMarco et al., Science (1991)253:789). Myotrophin, a 12.5 kDa protein having a key role in theinitiation of cardiac hypertrophy, comprises ankyrin repeats. Theankyrin repeats are characteristic of a hairpin-like protruding tipfollowed by a helix-turn-helix motif. The V-shaped helix-turn-helix ofthe repeats stack sequentially in bundles and are stabilized by compacthydrophobic cores, whereas the protruding tips are less ordered.

d) Eukaryotic Aspartyl Proteases (asp). Several of the validationsequences correspond to a sequence encoding a novel eukaryotic aspartylprotease. Aspartyl proteases, known as acid proteases, (EC 3.4.23.-) area widely distributed family of proteolytic enzymes (Foltmann B., EssaysBiochem. (1981) 17:52; Davies D. R., Annu. Rev. Biophys. Chem. (1990)19:189; Rao J. K. M., et al., Biochemistry (1991) 30:4663) known toexist in vertebrates, fungi, plants, retroviruses and some plantviruses. Aspartate proteases of eukaryotes are monomeric enzymes whichconsist of two domains. Each domain contains an active site centered ona catalytic aspartyl residue. The two domains most probably evolved fromthe duplication of an ancestral gene encoding a primordial domain.Currently known eukaryotic aspartyl proteases include: 1) Vertebrategastric pepsins A and C (also known as gastricsin); 2) Vertebratechymosin (rennin), involved in digestion and used for making cheese; 3)Vertebrate lysosomal cathepsins D (EC 3.4.23.5) and E (EC 3.4.23.34); 4)Mammalian renin (EC 3.4.23.15) whose function is to generate angiotensinI from angiotensinogen in the plasma; 5) Fungal proteases such asaspergillopepsin A (EC 3.4.23.18), candidapepsin (EC 3.4.23.24),mucoropepsin (EC 3.4.23.23) (mucor rennin), endothiapepsin (EC3.4.23.22), polyporopepsin (EC 3.4.23.29), and rhizopuspepsin (EC3.4.23.21); and 6) Yeast saccharopepsin (EC 3.4.23.25) (proteinase A)(gene PEP4). PEP4 is implicated in posttranslational regulation ofvacuolar hydrolases; 7) Yeast barrierpepsin (EC 3.4.23.35) (gene BAR1);a protease that cleaves alpha-factor and thus acts as an antagonist ofthe mating pheromone; and 8) Fission yeast sxa1 which is involved indegrading or processing the mating pheromones.

Most retroviruses and some plant viruses, such as badnaviruses, encodefor an aspartyl protease which is an homodimer of a chain of about 95 to125 amino acids. In most retroviruses, the protease is encoded as asegment of a polyprotein which is cleaved during the maturation processof the virus. It is generally part of the pol polyprotein and, morerarely, of the gag polyprotein. Because the sequence around the twoaspartates of eukaryotic aspartyl proteases and around the single activesite of the viral proteases is conserved, a single signature pattern canbe used to identify members of both groups of proteases.

e) ATPases Associated with Various Cellular Activities (ATPases).Several of the validation sequences, correspond to a sequence thatencodes a novel member of the “ATPases Associated with diverse cellularActivities” (AAA) protein family. The AAA protein family is composed ofa large number of ATPases that share a conserved region of about 220amino acids that contains an ATP-binding site (Froehlich et al., J. CellBiol. (1991) 114:443; Erdmann et al. Cell (1991) 64:499; Peters et al.,EMBO J. (1990) 9:1757; Kunau et al., Biochimie (1993) 75:209-224;Confalonieri et al., BioEssays (1995) 17:639;http://yeamob.pci.chemie.uni-tuebingen.de/AAA/Description.html). Theproteins that belong to this family either contain one or two AAAdomains.

Proteins containing two AAA domains include: 1) Mammalian and drosophilaNSF (N-ethylmaleimide-sensitive fusion protein) and the fungal homolog,SEC18, which are involved in intracellular transport between theendoplasmic reticulum and Golgi, as well as between different Golgicisternae; 2) Mammalian transitional endoplasmic reticulum ATPase(previously known as p97 or VCP), which is involved in the transfer ofmembranes from the endoplasmic reticulum to the golgi apparatus. ThisATPase forms a ring-shaped homooligomer composed of six subunits. Theyeast homolog, CDC48, plays a role in spindle pole proliferation; 3)Yeast protein PAS1 essential for peroxisome assembly and the relatedprotein PAS1 from Pichia pastoris; 4) Yeast protein AFG2; 5) Sulfolobusacidocaldarius protein SAV and Halobacterium salinarium cdcH, which maybe part of a transduction pathway connecting light to cell division.

Proteins containing a single AAA domain include: 1) Escherichia coli andother bacteria ftsH (or hflB) protein. FtsH is an ATP-dependent zincmetallopeptidase that degrades the heat-shock sigma-32 factor, and is anintegral membrane protein with a large cytoplasmic C-terminal domainthat contain both the AAA and the protease domains; 2) Yeast proteinYME1, a protein important for maintaining the integrity of themitochondrial compartment. YME1 is also a zinc-dependent protease; 3)Yeast protein AFG3 (or YTA10). This protein also contains an AAA domainfollowed by a zinc-dependent protease domain; 4) Subunits fromregulatory complex of the 26S proteasome (Hilt et al., Trends Biochem.Sci. (1996) 21:96), which is involved in the ATP-dependent degradationof ubiquitinated proteins, which subunits include: a) Mammalian 4 andhomologs in other higher eukaryotes, in yeast (gene YTA5) and fissionyeast (gene mts2); b) Mammalian 6 (TBP7) and homologs in other highereukaryotes and in yeast (gene YTA2); c) Mammalian subunit 7 (MSS1) andhomologs in other higher eukaryotes and in yeast (gene CIM5 or YTA3); d)Mammalian subunit 8 (P45) and homologs in other higher eukaryotes and inyeast (SUG1 or CIM3 or TBY1) and fission yeast (gene let1); e) Otherprobable subunits include human TBP1, which influences HIV geneexpression by interacting with the virus tat transactivator protein, andyeast YTA1 and YTA6; 5) Yeast protein BCS1, a mitochondrial proteinessential for the expression of the Rieske iron-sulfur protein; 6) Yeastprotein MSP1, a protein involved in intramitochondrial sorting ofproteins; 7) Yeast protein PAS8, and the corresponding proteins PAS5from Pichia pastoris and PAY4 from Yarrowia lipolytica; 8) Mouse proteinSKD1 and its fission yeast homolog (SpAC2G11.06); 9) Caenorhabditiselegans meiotic spindle formation protein mei-1; 10) Yeast protein SAP1′11) Yeast protein YTA7; and 12) Mycobacterium leprae hypotheticalprotein A2126A.

In general, the AAA domains in these proteins act as ATP-dependentprotein clamps (Confalonieri et al. (1995) BioEssays 17:639). Inaddition to the ATP-binding ‘A’ and ‘B’ motifs, which are located in theN-terminal half of this domain, there is a highly conserved regionlocated in the central part of the domain which was used in thedevelopment of the signature pattern.

f) Bcl-2 family (Bcl-2). SEQ ID NO:4248, and thus the correspondingsequence it validates, represents a polynucleotide encoding an apoptosisregulator protein of the Bcl-2, family. Active cell suicide (apoptosis)is induced by events such as growth factor withdrawal and toxins. It iscontrolled by regulators, which have either an inhibitory effect onprogrammed cell death (anti-apoptotic) or block the protective effect ofinhibitors (pro-apoptotic) (Vaux, 1993, Curr. Biol. 3:877-878, andWhite, 1996, Genes Dev. 10:2859-2869). Many viruses have found a way ofcountering defensive apoptosis by encoding their own anti-apoptosisgenes, preventing their target cells from dying prematurely.

All proteins belonging to the Bcl-2 family (Reed et al., 1996, Adv. Exp.Med. Biol. 406:99-112) contain either a BH1, BH2, BH3, or BH4 domain.All anti-apoptotic proteins contain BH1 and BH2 domains; some of themcontain an additional N-terminal BH4 domain (Bcl-2, Bcl-x(L), Bcl-w),which is never seen in pro-apoptotic proteins, except for Bcl-x(S). Onthe other hand, all pro-apoptotic proteins contain a BH3 domain (exceptfor Bad) necessary for dimerization with other proteins of Bcl-2 familyand crucial for their killing activity; some of them also contain BH1and BH2 domains (Bax, Bak). The BH3 domain is also present in someanti-apoptotic protein, such as Bcl-2 or Bcl-x(L). Proteins that areknown to contain these domains are listed below.

-   1. Vertebrate protein Bcl-2. Bcl-2 blocks apoptosis; it prolongs the    survival of hematopoietic cells in the absence of required growth    factors and also in the presence of various stimuli inducing    cellular death. Two isoforms of bcl-2 (alpha and beta) are generated    by alternative splicing. Bcl-2 is expressed in a wide range of    tissues at various times during development. It forms heterodimers    with the Bax proteins.-   2. Vertebrate protein Bcl-x. Two isoforms of Bcl-x (Bcl-x(L) and    Bcl-x(S)) are generated by alternative splicing. While the longer    product (Bcl-x(L)) can protect a growth-factor-dependent cell line    from apoptosis, the shorter form blocks the protective effect of    Bcl-2 and Bcl-x(L) and acts as an anti-anti-apoptosis protein.-   3. Mammalian protein Bax. Bax blocks the anti-apoptosis ability of    Bcl-2 with which it forms heterodimers. There is no evidence that    Bax has any activity in the absence of Bcl-2. Three isoforms of bax    (alpha, beta and gamma) are generated by alternative splicing.-   4. Mammalian protein Bak, which promotes cell death and counteracts    the protection from apoptosis provided by Bcl-2.-   5. Mammalian protein Bcl-w, which promotes cell survival.-   6. Mammalian protein bad, which promotes cell death, and counteracts    the protection from apoptosis provided by Bcl-x(L), but not that of    Bcl-2.-   7. Human protein Bik, which promotes cell death, but cannot    counteract the protection from apoptosis provided by Bcl-2.-   8. Mouse protein Bid, which induces caspases and apoptosis, and    counteracts the protection from apoptosis provided by Bcl-2.-   9. Human induced myeloid leukemia cell differentiation protein MCL1.    MCL1 is probably involved in programming of differentiation and    concomitant maintenance of viability but not proliferation. Its    expression increases early during phorbol ester induced    differentiation in myeloid leukemia cell line ML-1.-   10. Mouse hemopoietic-specific early response protein A1.-   11. Mammalian activator of apoptosis Harakiri (Inohara et al., 1997,    EMBO J. 16:1686-1694) (also known as neuronal death protein Dp5).    This is a small protein of 92-residues that activates apoptosis. It    contains a BH3 domain, but no BH1, BH2 or BH4 domains.

The following consensus patterns have been developed for the four BHdomains:

g) Bromodomain (bromodomain). Some SEQ ID NOS represent polynucleotidesencoding a polypeptide having a bromodomain region (Haynes et al., 1992,Nucleic Acids Res. 20:2693-2603, Tamkun et al., 1992, Cell 68:561-572,and Tamkun, 1995, Curr. Opin. Genet. Dev. 5:473-477), which is aconserved region of about 70 amino acids found in the followingproteins: 1) Higher eukaryotes transcription initiation factor TFIID 250Kd subunit (TBP-associated factor p250) (gene CCG1); P250 is associatedwith the TFIID TATA-box binding protein and seems essential forprogression of the G1 phase of the cell cycle. 2) Human RING3, a proteinof unknown function encoded in the MHC class II locus; 3) MammalianCREB-binding protein (CBP), which mediates cAMP-gene regulation bybinding specifically to phosphorylated CREB protein; 4) Mammalianhomologs of brahma, including three brahma-like human: SNF2a(hBRM),SNF2b, and BRG1; 5) Human BS69, a protein that binds to adenovirus E1Aand inhibits E1A transactivation; 6) Human peregrin (or Br140).

The bromodomain is thought to be involved in protein-proteininteractions and may be important for the assembly or activity ofmulticomponent complexes involved in transcriptional activation.

h) Basic Region Plus Leucine Zipper Transcription Factors (BZIP). SomeSEQ ID NOS, and thus the corresponding sequences these sequencesvalidate, represent polynucleotides encoding a novel member of thefamily of basic region plus leucine zipper transcription factors. ThebZIP superfamily (Hurst, Protein Prof. (11995) 2:105; and Ellenberger,Curr. Opin. Struct. Biol. (1994) 4:12) of eukaryotic DNA-bindingtranscription factors encompasses proteins that contain a basic regionmediating sequence-specific DNA-binding followed by a leucine zipperrequired for dimerization. Members of the family include transcriptionfactor AP-1, which binds selectively to enhancer elements in the ciscontrol regions of SV40 and metallothionein IIA. AP-1, also known asc-jun, is the cellular homolog of the avian sarcoma virus 17 (ASV17)oncogene v-jun.

Other members of this protein family include jun-B and jun-D, probabletranscription factors that are highly similar to jun/AP-1; the fosprotein, a proto-oncogene that forms a non-covalent dimer with c-jun;the fos-related proteins fra-1, and fos B; and mammalian cAMP responseelement (CRE) binding proteins CREB, CREM, ATF-1, ATF-3, ATF-4, ATF-5,ATF-6 and LRF-1.

i) Cyclins (cyclin). Some SEQ ID NOS represent polynucleotides encodingcyclins, and SEQ ID NO:899 and 900, respectively, show the correspondingfull-length polynucleotides. SEQ ID NO:901 and 902 show, respectively,the translations of SEQ ID NO:899 and 900. Cyclins (Nurse, 1990, Nature344:503-508; Norbury et al., 1991, Curr. Biol. 1:23-24; and Lew et al.,1992, Trends Cell Biol. 2:77-81) are eukaryotic proteins that play anactive role in controlling nuclear cell division cycles. There are twomain groups of cyclins. G2/M cyclins are essential for the control ofthe cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulatesteadily during G2 and are abruptly destroyed as cells exit from mitosis(at the end of the M-phase). G1/S cyclins are essential for the controlof the cell cycle at the G1/S (start) transition.

j) Eukaryotic thiol (cysteine) proteases active sites (Cys-protease).Some SEQ ID NOS, and thus also the sequences they validate, repreasentpolynucleotides encoding proteins having a eukaryotic thiol (cysteine)protease active site. Eukaryotic thiol proteases (Dufour E., Biochimie(1988) 70:1335); are a family of proteolytic enzymes which contain anactive site cysteine. Catalysis proceeds through a thioesterintermediate and is facilitated by a nearby histidine side chain; anasparagine completes the essential catalytic triad. The proteases thatbelong to this family are: 1) vertebrate lysosomal cathepsins B(Kirschke H., et al., Protein Prof. (1995) 2:1587-1643); 2) vertebratelysosomal dipeptidyl peptidase I (also known as cathepsin C) (KirschkeH., et al., supra); 3) vertebrate calpains (Calpains are intracellularcalcium-activated thiol protease that contain both an N-terminalcatalytic domain and a C-terminal calcium-binding domain); 4) mammaliancathepsin K, which seems involved in osteoclastic bone resorption (ShiG.-P., et al., FEBS Lett. (1995) 357:129); 5) human cathepsin O ([4]Velasco G., Ferrando A. A., Puente X. S., Sanchez L. M., Lopez-Otin C.J. Biol. Chem. (1994) 269:27136); 6) bleomycin hydrolase (whichcatalyzes the inactivation of the antitumor drug BLM (a glycopeptide));7) Plant enzymes such as: barley aleurain, EP-B1/B4; kidney bean EP-C1,rice bean SH-EP; kiwi fruit actinidin; papaya latex papin, chymopapain,caricain, and proteinase IV; pea turgor-responsive protein 15A;pineapple stem bromelain; rape COT44; rice oryzain alpha, beta, andgamma; tomato low-temperature induced, Arabidopsis thaliana A494, RD19Aand RD21A; 8) House-dust mites allergens DerP1 and EurM1; 9) cathepsinB-like proteinases from the worms Caenorhabditis elegans (genes gcp-1,cpr-3, cpr-4, cpr-5 and cpr-6), Schistosoma mansoni (antigen SM31) andJaponica (antigen SJ31), Haemonchus contortus (genes AC-1 and AC-2), andOstertagia ostertagi (CP-1 and CP-3); 10) slime mold cysteineproteinases CP1 and CP2; 11) cruzipain from Trypanosoma cruzi andbrucei; 12) throphozoite cysteine proteinase (TCP) from variousPlasmodium species; 13) proteases from Leishmania mexicana, Theileriaannulata and Theileria parva; 14) Baculoviruses cathepsin-like enzyme(v-cath); 15) Drosophila small optic lobes protein (gene sol), aneuronal protein that contains a calpain-like domain; 16) yeast thiolprotease BLH1/YCP1/LAP3; 17) Caenorhabditis elegans hypothetical proteinC06G4.2, a calpain-like protein.

In addition, two bacterial peptidases are also part of this family: 1)aminopeptidase C from Lactococcus lactis (gene pepC) (Chapot-Chartier M.P., et al., Appl. Environ. Microbiol. (1993) 59:330); and 2) thiolprotease tpr from Porphyromonas gingivalis. Three other proteins arestructurally related to this family, but may have lost their proteolyticactivity. These include: 1) soybean oil body protein P34 (which has itsactive site cysteine replaced by a glycine); 2) rat testin (which is asertoli cell secretory protein highly similar to cathepsin L but withthe active site cysteine is replaced by a serine); and 3) Plasmodiumfalciparum serine-repeat protein (SERA) (which is the major blood stageantigen and possesses a C-terminal thiol-protease-like domain (HigginsD. G., et al., Nature (1989) 340:604), with the active site cysteine isreplaced by a serine).

k) Phorbol Esters/Diacylglycerol Binding (DAG_PE_bind). One SEQrepresents a polynucleotide encoding a protein belonging to the familyincluding phorbol esters/diacylglycerol binding proteins. Diacylglycerol(DAG) is an important second messenger. Phorbol esters (PE) areanalogues of DAG and potent tumor promoters that cause a variety ofphysiological changes when administered to both cells and tissues. DAGactivates a family of serine/threonine protein kinases, collectivelyknown as protein kinase C (PKC) (Azzi et al., Eur. J. Biochem. (1992)208:547). Phorbol esters can directly stimulate PKC. The N-terminalregion of PKC, known as C1, has been shown (Ono et al., Proc. Natl.Acad. Sci. USA (1989) 86:4868) to bind PE and DAG in a phospholipid andzinc-dependent fashion. The C1 region contains one or two copies(depending on the isozyme of PKC) of a cysteine-rich domain about 50amino-acid residues long and essential for DAG/PE-binding. Such a domainhas also been found in, for example, the following proteins.

(1) Diacylglycerol kinase (EC 2.7.1.107) (DGK) (Sakane et al., Nature(1990) 344:345), the enzyme that converts DAG into phosphatidate. Itcontains two copies of the DAG/PE-binding domain in its N-terminalsection. At least five different forms of DGK are known in mammals; and

(2) N-chimaerin, a brain specific protein which shows sequencesimilarities with the BCR protein at its C-terminal part and contains asingle copy of the DAG/PE-binding domain at its N-terminal part. It hasbeen shown (Ahmed et al., Biochem. J. (1990) 272:767, and Ahmed et al.,Biochem. J. (1991) 280:233) to be able to bind phorbol esters.

The DAG/PE-binding domain binds two zinc ions; the ligands of thesemetal ions are probably the six cysteines and two histidines that areconserved in this domain. The signature pattern completely spans theDAG/PE domain.

l) DEAD and DEAH box families ATP-dependent helicases signatures(Dead_box_helic). Some SEQ ID NOS represent polynucleotides encoding anovel member of the DEAD box family. A number of eukaryotic andprokaryotic proteins have been characterized (Schmid S. R., et al., Mol.Microbiol. (1992) 6:283; Linder P., et al., Nature (1989) 337:121;Wassarman D. A., et al., Nature (1991) 349:463) on the basis of theirstructural similarity. All are involved in ATP-dependent, nucleic-acidunwinding. Proteins currently known to belong to this family are:

1) Initiation factor eIF-4A. Found in eukaryotes, this protein is asubunit of a high molecular weight complex involved in 5′cap recognitionand the binding of mRNA to ribosomes. It is an ATP-dependentRNA-helicase.

2) PRP5 and PRP28. These yeast proteins are involved in variousATP-requiring steps of the pre-mRNA splicing process.

3) P110, a mouse protein expressed specifically during spermatogenesis.

4) An3, a Xenopus putative RNA helicase, closely related to P110.

5) SPP81/DED1 and DBP1, two yeast proteins involved in pre-mRNA splicingand related to P110.

6) Caenorhabditis elegans helicase glh-1.

7) MSS116, a yeast protein required for mitochondrial splicing.

8) SPB4, a yeast protein involved in the maturation of 25S ribosomalRNA.

9) p68, a human nuclear antigen. p68 has ATPase and DNA-helicaseactivities in vitro. It is involved in cell growth and division.

10) Rm62 (p62), a Drosophila putative RNA helicase related to p68.

11) DBP2, a yeast protein related to p68.

12) DHH1, a yeast protein.

13) DRS1, a yeast protein involved in ribosome assembly.

14) MAK5, a yeast protein involved in maintenance of dsRNA killerplasmid.

15) ROK1, a yeast protein.

16) ste13, a fission yeast protein.

17) Vasa, a Drosophila protein important for oocyte formation andspecification of embryonic posterior structures.

18) Me31B, a Drosophila maternally expressed protein of unknownfunction.

19) dbpA, an Escherichia coli putative RNA helicase.

20) deaD, an Escherichia coli putative RNA helicase which can suppress amutation in the rpsB gene for ribosomal protein S2.

21) rhlB, an Escherichia coli putative RNA helicase.

22) rhlE, an Escherichia coli putative RNA helicase.

23) rmB, an Escherichia coli protein that shows RNA-dependent ATPaseactivity, which interacts with 23S ribosomal RNA.

24) Caenorhabditis elegans hypothetical proteins T26G10.1, ZK512.2 andZK686.2.

25) Yeast hypothetical protein YHR065c.

26) Yeast hypothetical protein YHR169w.

27) Fission yeast hypothetical protein SpAC31A2.07c.

28) Bacillus subtilis hypothetical protein yxiN.

All of the above proteins share a number of conserved sequence motifs.Some of them are specific to this family while others are shared byother ATP-binding proteins or by proteins belonging to the helicases‘superfamily’ (Hodgman T. C., Nature (1988) 333:22 and Nature (1988)333:578 (Errata); http://www.expasy.ch/www/linder/HELICASES_TEXT.html).One of these motifs, called the ‘D-E-A-D-box’, represents a specialversion of the B motif of ATP-binding proteins. Some other proteinsbelong to a subfamily which have His instead of the second Asp and arethus said to be ‘D-E-A-H-box’ proteins (Wassarman D. A., et al., Nature(1991) 349:463; Harosh I., et al., Nucleic Acids Res. (1991) 19:6331;Koonin E. V., et al., J. Gen. Virol. (1992) 73:989). Proteins currentlyknown to belong to this DEAH subfamily are:

1) PRP2, PRP16, PRP22 and PRP43. These yeast proteins are all involvedin various ATP-requiring steps of the pre-mRNA splicing process. 2)Fission yeast prh1, which my be involved in pre-mRNA splicing. 3)Male-less (mle), a Drosophila protein required in males, for dosagecompensation of X chromosome linked genes. 4) RAD3 from yeast. RAD3 is aDNA helicase involved in excision repair of DNA damaged by UV light,bulky adducts or cross-linking agents. Fission yeast rad15 (rhp3) andmammalian DNA excision repair protein XPD (ERCC-2) are the homologs ofRAD3. 5) Yeast CHL1 (or CTF1), which is important for chromosometransmission and normal cell cycle progression in G(2)/M. 6) Yeast TPS1.7) Yeast hypothetical protein YKL078w. 8) Caenorhabditis eleganshypothetical proteins C06E1.10 and K03H1.2. 9) Poxviruses' earlytranscription factor 70 Kd subunit which acts with RNA polymerase toinitiate transcription from early gene promoters. 10) I8, a putativevaccinia virus helicase. 11) hrpA, an Escherichia coli putative RNAhelicase.

m) EF Hand (EFhand). Several of the validation sequences, and thus thesequences they validate, correspond to polynucleotides encoding a novelprotein in the family of EF-hand proteins. Many calcium-binding proteinsbelong to the same evolutionary family and share a type ofcalcium-binding domain known as the EF-hand (Kawasaki et al., Protein.Prof. (1995) 2:305-490). This type of domain consists of a twelveresidue loop flanked on both sides by a twelve residue alpha-helicaldomain. In an EF-hand loop the calcium ion is coordinated in apentagonal bipyramidal configuration. The six residues involved in thebinding are in positions 1, 3, 5, 7, 9 and 12; these residues aredenoted by X, Y, Z, −Y, −X and −Z. The invariant Glu or Asp at position12 provides two oxygens for liganding Ca (bidentate ligand).

Proteins known to contain EF-hand regions include: Calmodulin (Ca=4,except in yeast where Ca=3) (“Ca=” indicates approximate number ofEF-hand regions); diacylglycerol kinase (EC 2.7.1.107) (DGK) (Ca=2); 2)FAD-dependent glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) frommammals (Ca=1); guanylate cyclase activating protein (GCAP) (Ca=3); MIFrelated proteins 8 (MRP-8 or CFAG) and 14 (MRP-14) (Ca=2); myosinregulatory light chains (Ca=I); oncomodulin (Ca=2); osteonectin(basement membrane protein BM-40) (SPARC); and proteins that contain an“osteonectin” domain (QR1, matrix glycoprotein SC1).

n) Ets Domain (Ets_Nterm). One SEQ ID NO, and thus the sequence itvalidates, represents a polynucleotide encoding a polypeptide withN-terminal homology in ETS domain. Proteins of this family contain aconserved domain, the “ETS-domain,” that is involved in DNA binding. Thedomain appears to recognize purine-rich sequences; it is about 85 to 90amino acids in length, and is rich in aromatic and positively chargedresidues (Wasylyk, et al., Eur. J. Biochem. (1993) 211:718).

The ets gene family encodes a novel class of DNA-binding proteins, eachof which binds a specific DNA sequence. These proteins comprise an etsdomain that specifically interacts with sequences containing the commoncore tri-nucleotide sequence GGA. In addition to an ets domain, nativeets proteins comprise other sequences which can modulate the biologicalspecificity of the protein. Ets genes and proteins are involved in avariety of essential biological processes including cell growth,differentiation and development, and three members are implicated inoncogenic process.

o) Type II fibronectin collagen-binding domain (FntypeII). A few of thevalidation sequences, and thus the sequences they validate, representpolynucleotides encoding a polypeptide having a type II fibronectincollagen binding domain. Fibronectin is a plasma protein that binds cellsurfaces and various compounds including collagen, fibrin, heparin, DNA,and actin. The major part of the sequence of fibronectin consists of therepetition of three types of domains, which are called type I, II, andIII (Skorstengaard K., et al., Eur. J. Biochem. (1986) 161:441). Type IIdomain is approximately forty residues long, contains four conservedcysteines involved in disulfide bonds and is part of thecollagen-binding region of fibronectin. In fibronectin the type IIdomain is duplicated. Type II domains have also been found in thefollowing proteins: 1) blood coagulation factor XII (Hageman factor) (1copy); 2) bovine seminal plasma proteins PDC-109 (BSP-A1/A2) and BSP-A3(Seidah N. G., et al., Biochem. J. (1987) 243:195. (twice); 3)cation-independent mannose-6-phosphate receptor (which is also theinsulin-like growth factor II receptor) Kornfeld S., Annu. Rev. Biochem.(1992) 61:307) (1 copy); 4) Mannose receptor of macrophages (Taylor M.E., et al., J. Biol. Chem. (1990) 265:12156) (1 copy); 5) 180 Kdsecretory phospholipase A2 receptor (1 copy) Lambeau G., et al., J.Biol. Chem. (1994) 269:1575; 6) DEC-205 receptor (1 copy); 6) Jiang W.,et al., Nature (1995) 375:151); 7) 72 Kd type IV collagenase (EC3.4.24.24) (MMP-2) (Collier I. E., et al., J. Biol. Chem. (1988)263:6579) (3 copies); 7) 92 Kd type IV collagenase (EC 3.4.24.24)(MMP-9) (3 copies); 8) Hepatocyte growth factor activator (Miyazawa K.,et al., J. Biol. Chem. (1993) 268:10024) (1 copy).

p) G-Protein Alpha Subunit (G-alpha). Several of the validationsequences, and thus the sequences they validate, correspond to a geneencoding a novel polypeptide of the G-protein alpha subunit family.Guanine nucleotide binding proteins (G-proteins) are a family ofmembrane-associated proteins that couple extracellularly-activatedintegral-membrane receptors to intracellular effectors, such as ionchannels and enzymes that vary the concentration of second messengermolecules. G-proteins are composed of 3 subunits (alpha, beta and gamma)which, in the resting state, associate as a trimer at the inner face ofthe plasma membrane. The alpha subunit has a molecule of guanosinediphosphate (GDP) bound to it. Stimulation of the G-protein by anactivated receptor leads to its exchange for GTP (guanosinetriphosphate). This results in the separation of the alpha from the betaand gamma subunits, which always remain tightly associated as a dimer.Both the alpha and beta-gamma subunits are then able to interact witheffectors, either individually or in a cooperative manner. The intrinsicGTPase activity of the alpha subunit hydrolyses the bound GTP to GDP.This returns the alpha subunit to its inactive conformation and allowsit to reassociate with the beta-gamma subunit, thus restoring the systemto its resting state.

G-protein alpha subunits are 350-400 amino acids in length and havemolecular weights in the range 40-45 kDa. Seventeen distinct types ofalpha subunit have been identified in mammals. These fall into 4 maingroups on the basis of both sequence similarity and function: alpha-s,alpha-q, alpha-i and alpha-12 (Simon et al., Science (1993) 252:802).Many alpha subunits are substrates for ADP-ribosylation by cholera orpertussis toxins. They are often N-terminally acylated, usually withmyristate and/or palmitoylate, and these fatty acid modifications areprobably important for membrane association and high-affinityinteractions with other proteins. The atomic structure of the alphasubunit of the G-protein involved in mammalian vision, transducin, hasbeen elucidated in both GTP- and GDB-bound forms, and shows considerablesimilarity in both primary and tertiary structure in thenucleotide-binding regions to other guanine nucleotide binding proteins,such as p21-ras and EF-Tu.

q) Helicases conserved C-terminal domain (helicase C). Some SEQ ID NOS,and thus the sequences they validate, represent polynucleotides encodingnovel members of the DEAD/H helicase family. The DEAD and DEAH familiesare described above.

r) Homeobox domain (homeobox). One SEQ ID NO, and thus the sequence itvalidates, represents a polynucleotide encoding a protein having ahomeobox domain. The ‘homeobox’ is a protein domain of 60 amino acids(Gehring In: Guidebook to the Homebox Genes, Duboule D., Ed., pp1-10,Oxford University Press, Oxford, (1994); Buerglin In: Guidebook to theHomebox Genes, pp25-72, Oxford University Press, Oxford, (1994); GehringTrends Biochem. Sci. (1992) 17:277-280; Gehring et al Annu. Rev. Genet.(1986) 20:147-173; Schofield Trends Neurosci. (1987) 10:3-6;http://copan.bioz.unibas.ch/homeo.html) first identified in number ofDrosophila homeotic and segmentation proteins. It is extremely wellconserved in many other animals, including vertebrates. This domainbinds DNA through a helix-turn-helix type of structure. Several proteinsthat contain a homeobox domain play an important role in development.Most of these proteins are sequence-specific DNA-binding transcriptionfactors. The homeobox domain is also very similar to a region of theyeast mating type proteins. These are sequence-specific DNA-bindingproteins that act as master switches in yeast differentiation bycontrolling gene expression in a cell type-specific fashion.

A schematic representation of the homeobox domain is shown below. Thehelix-turn-helix region is shown by the symbols ‘H’ (for helix), and ‘t’(for turn).

The pattern detects homeobox sequences 24 residues long and spanspositions 34 to 57 of the homeobox domain.

x) MAP kinase kinase (mkk). Several validation sequences, and thus thesequences they validate, represent novel members of the MAP kinasekinase family. MAP kinases (MAPK) are involved in signal transduction,and are important in cell cycle and cell growth controls. The MAP kinasekinases (MAPKK) are dual-specificity protein kinases which phosphorylateand activate MAP kinases. MAPKK homologues have been found in yeast,invertebrates, amphibians, and mammals. Moreover, the MAPKK/MAPKphosphorylation switch constitutes a basic module activated in distinctpathways in yeast and in vertebrates. MAPKK regulation studies have ledto the discovery of at least four MAPKK convergent pathways in higherorganisms. One of these is similar to the yeast pheromone responsepathway which includes the ste11 protein kinase. Two other pathwaysrequire the activation of either one or both of the serine/threoninekinase-encoded oncogenes c-Raf-1 and c-Mos. Additionally, severalstudies suggest a possible effect of the cell cycle control regulatorcyclin-dependent kinase 1 (cdc2) on MAPKK activity. Finally, MAPKKs areapparently essential transducers through which signals must pass beforereaching the nucleus. For review, see, e.g., Biologique Biol Cell (1993)79:193-207; Nishida et al., Trends Biochem Sci (1993) 18:128-31;Ruderman Curr Opin Cell Biol (1993) 5:207-13; Dhanasekaran et al.,Oncogene (1998) 17:1447-55; Kiefer et al., Biochem Soc Trans (1997)25:491-8; and Hill, Cell Signal (1996) 8:533-44.

y) 3′5′-cyclic nucleotide phosphodiesterases signature (PDEase). One SEQID NO, and thus the sequence it validates, represents a polynucleotideencoding a novel 3′5′-cyclic nucleotide phosphodiesterases (PDEases).PDEases catalyze the hydrolysis of cAMP or cGMP to the correspondingnucleoside 5′ monophosphates (Charbonneau H., et al, Proc. Natl. Acad.Sci. U.S.A. (1986) 83:9308). There are at least seven differentsubfamilies of PDEases (Beavo J. A., et al., Trends Pharmacol. Sci.(1990) 11:150; http://weber.u.washington.edu/˜pde/: 1) Type 1,calmodulin/calcium-dependent PDEases; 2) Type 2, cGMP-stimulatedPDEases; 3) Type 3, cGMP-inhibited PDEases; 4) Type 4, cAMP-specificPDEases; 5) Type 5, cGMP-specific PDEases; 6) Type 6,rhodopsin-sensitive cGMP-specific PDEases; and 7) Type 7, High affinitycAMP-specific PDEases.

All PDEase forms share a conserved domain of about 270 residues.

z) Protein Kinase (protkinase). Several validation sequences, and thusthe sequences they validate, represent polynucleotides encoding proteinkinases. Protein kinases catalyze phosphorylation of proteins in avariety of pathways, and are implicated in cancer. Eukaryotic proteinkinases (Hanks S. K., et al., FASEB J. (1995) 9:576; Hunter T., Meth.Enzymol. (1991) 200:3; Hanks S. K., et al., Meth. Enzymol. (1991)200:38; Hanks S. K., Curr. Opin. Struct. Biol. (1991) 1:369; Hanks S.K., et al., Science (1988) 241:42) are enzymes that belong to a veryextensive family of proteins which share a conserved catalytic corecommon to both serine/threonine and tyrosine protein kinases. There area number of conserved regions in the catalytic domain of proteinkinases. Two of the conserved regions are the basis for the signaturepattern in the protein kinase profile. The first region, which islocated in the N-terminal extremity of the catalytic domain, is aglycine-rich stretch of residues in the vicinity of a lysine residue,which has been shown to be involved in ATP binding. The second region,which is located in the central part of the catalytic domain, contains aconserved aspartic acid residue which is important for the catalyticactivity of the enzyme (Knighton D. R., et al., Science (1991) 253:407).The protein kinase profile includes two signature patterns for thissecond region: one specific for serine/threonine kinases and the otherfor tyrosine kinases. A third profile is based on the alignment in(Hanks S. K., et al., FASEB J. (1995) 9:576) and covers the entirecatalytic domain.

The protein kinase profile also detects receptor guanylate cyclases and2-5A-dependent ribonucleases. Sequence similarities between these twofamilies and the eukaryotic protein kinase family have been noticedpreviously. The profile also detects Arabidopsis thaliana kinase-likeprotein TMKL1 which seems to have lost its catalytic activity.

If a protein analyzed includes the two of the above protein kinasesignatures, the probability of it being a protein kinase is close to100%. Eukaryotic-type protein kinases have also been found inprokaryotes such as Myxococcus xanthus (Munoz-Dorado J., et al., Cell(1991) 67:995) and Yersinia pseudotuberculosis. The patterns shown abovehas been updated since their publication in (Bairoch A., et al., Nature(1988) 331:22).

aa) Ras family proteins (ras). One SEQ ID NO, and thus the sequence itvalidates, represent polynucleotides encoding the ras family of smallGTP/GDP-binding proteins (Valencia et al., 1991, Biochemistry30:4637-4648). Ras family members generally require a specific guaninenucleotide exchange factor (GEF) and a specific GTPase activatingprotein (GAP) as stimulators of overall GTPase activity. Amongras-related proteins, the highest degree of sequence conservation isfound in four regions that are directly involved in guanine nucleotidebinding. The first two constitute most of the phosphate and Mg2+ bindingsite (PM site) and are located in the first half of the G-domain. Theother two regions are involved in guanosine binding and are located inthe C-terminal half of the molecule. Motifs and conserved structuralfeatures of the ras-related proteins are described in Valencia et al.,1991, Biochemistry 30:4637-4648.

bb) Thioredoxin family active site (Thioredox). One SEQ ID NO, and thusthe sequence it validates, represent a polynucleotide encoding a proteinhaving a thioredoxin family active site. Thioredoxins (Holmgren A.,Annu. Rev. Biochem. (1985) 54:237; Gleason F. K., et al., FEMSMicrobiol. Rev. (1988) 54:271; Holmgren A. J. Biol. Chem. (1989)264:13963; Eklund H., et al. Proteins (1991) 11:13) are small proteinsof approximately one hundred amino-acid residues which participate invarious redox reactions via the reversible oxidation of an active centerdisulfide bond. They exist in either a reduced form or an oxidized formwhere the two cysteine residues are linked in an intramoleculardisulfide bond. Thioredoxin is present in prokaryotes and eukaryotes andthe sequence around the redox-active disulfide bond is well conserved.

A number of eukaryotic proteins contain domains evolutionary related tothioredoxin, and all of them are protein disulphide isomerases (PDI).PDI (Freedman R. B., et al., Biochem. Soc. Trans. (1988) 16:96;Kivirikko K. I., et al., FASEB J. (1989) 3:1609; Freedman R. B., et al.Trends Biochem. Sci. (1994) 19:331) is an endoplasmic reticulum enzymethat catalyzes the rearrangement of disulfide bonds in various proteins.The various forms of PDI which are currently known are: 1) PDI majorisozyme; a multifunctional protein that also function as the betasubunit of prolyl 4-hydroxylase (EC 1.14.11.2), as a component ofoligosaccharyl transferase (EC 2.4.1.119), as thyroxine deiodinase, asglutathione-insulin transhydrogenase, and as a thyroid hormone-bindingprotein; 2) ERp60 (ER-60; 58 Kd microsomal protein), which is aprotease; 3) ERp72; and 4) P5.

cc) TNFR/NGFR family cysteine-rich region (TNFR_c6). One SEQ ID NO, andthus the sequence it validates, represent a polynucleotide encoding aprotein having a TNFR/NGFR family cysteine-rich region. A number ofproteins, some of which are known to be receptors for growth factors,have been found to contain a cysteine-rich domain of about 110 to 160amino acids in their N-terminal part, that can be subdivided into four(or in some cases, three) modules of about 40 residues containing 6conserved cysteines. Proteins known to belong to this family (Mallet S.,et al., Immunol. Today (1991) 12:220; Sprang S. R., Trends Biochem. Sci.(1990) 15:366; Krammer P. H., et al., Curr. Biol. (1992)2:383; Bazan J.F., Curr. Biol. (1993)3:603) are: 1) Tumor Necrosis Factor type I andtype II receptors (TNFR) (Both receptors bind TNF-alpha and TNF-beta,but are only similar in the cysteine-rich region.); 2) Shope fibromavirus soluble TNF receptor (protein T2); 3) Lymphotoxin alpha/betareceptor; 4) Low-affinity nerve growth factor receptor (LA-NGFR); 5)CD40 (BpS0), the receptor for the CD40L (or TRAP) cytokine; 6) CD27, thereceptor for the CD27L cytokine; 8) CD30, the receptor for the CD30Lcytokine; 9) T-cell protein 4-1BB, the receptor for the 4-1BBL putativecytokine; 10) FAS antigen (or APO-1), the receptor for FASL, a proteininvolved in apoptosis (programmed cell death); 11) T-cell antigen OX40,the receptor for the OX40L cytokine; 12) Wsl-1, a receptor (for a yetundefined ligand) that mediates apoptosis; 13) Vaccinia virus proteinA53 (SalF19R).

The six cysteines all involved in intrachain disulfide bonds (Banner D.W., et al, Cell (1993) 73:431). A schematic representation of thestructure of the 40 residue module of these receptors is shown below:

where ‘C’ represents the conserved cysteine involved in a disulfidebond. The signature pattern for the cysteine-rich region is based mainlyon the position of the six conserved cysteines in each of the repeats:Consensus pattern:C-x(4,6)-[FYH]-x(5,10)-C-x(0,2)-C-x(2,3)-C-x(7,11)-C-x(4,6)-[DNEQSKP]-x(2)-C(where the six C's are involved in disulfide bonds).

dd) Four Transmembrane Integral Membrane Proteins (transmembrane4).Several of the validation sequences, and thus the sequences theyvalidate, correspond to a sequence encoding a polypeptide that is amember of the 4 transmembrane segments integral membrane protein family(transmembrane 4 family). The transmembrane 4 family of proteinsincludes a number of evolutionarily-related eukaryotic cell surfaceantigens (Levy et al., J. Biol. Chem., (1991) 266:14597; Tomlinson etal., Eur. J. Immunol. (1993) 23:136; Barclay et al. The leucocyteantigen factbooks. (1993) Academic Press, London/San Diego). Theproteins belonging to this family include: 1) Mammalian antigen CD9(MIC3), which is involved in platelet activation and aggregation; 2)Mammalian leukocyte antigen CD37, expressed on B lymphocytes; 3)Mammalian leukocyte antigen CD53 (OX-44), which is implicated in growthregulation in hematopoietic cells; 4) Mammalian lysosomal membraneprotein CD63 (melanoma-associated antigen ME491; antigen AD1); 5)Mammalian antigen CD81 (cell surface protein TAPA-1), which isimplicated in regulation of lymphoma cell growth; 6) Mammalian antigenCD82 (protein R2; antigen C33; Kangai 1 (KAI1)), which associates withCD4 or CD8 and delivers costimulatory signals for the TCR/CD3 pathway;7) Mammalian antigen CD151 (SFA-1; platelet-endothelial tetraspanantigen 3 (PETA-3)); 8) Mammalian cell surface glycoprotein A15(TALLA-1; MXS1); 9) Mammalian novel antigen 2 (NAG-2); 10) Humantumor-associated antigen CO-029; 11) Schistosoma mansoni and japonicum23 Kd surface antigen (SM23/SJ23).

The members of the 4 transmembrane family share several characteristics.First, they all are apparently type III membrane proteins, which areintegral membrane proteins containing an N-terminal membrane-anchoringdomain which is not cleaved during biosynthesis and which functions bothas a translocation signal and as a membrane anchor. The family membersalso contain three additional transmembrane regions, at least sevenconserved cysteines residues, and are of approximately the same size(218 to 284 residues). These proteins are collectively know as the“transmembrane 4 superfamily” (TM4) because they span plasma membranefour times.A schematic diagram of the domain structure of these proteins is asfollows:

where Cyt is the cytoplasmic domain, TMa is the transmembrane anchor;TM2 to TM4 represents transmembrane regions 2 to 4, ‘C’ are conservedcysteines, and ‘*’ indicates the position of the consensus pattern. Theconsensus pattern spans a conserved region including two cysteineslocated in a short cytoplasmic loop between two transmembrane domains:

ee) Trypsin (trypsin). Some SEQ ID NOS, and thus the sequences theyvalidate, correspond to novel serine proteases of the trypsin family.The catalytic activity of the serine proteases from the trypsin familyis provided by a charge relay system involving an aspartic acid residuehydrogen-bonded to a histidine, which itself is hydrogen-bonded to aserine. The sequences in the vicinity of the active site serine andhistidine residues are well conserved in this family of proteases(Brenner S., Nature (1988) 334:528). Proteases known to belong to thetrypsin family include: 1) Acrosin; 2) Blood coagulation factors VII,IX, X, XI and XII, thrombin, plasminogen, and protein C; 3) Cathepsin G;4) Chymotrypsins; 5) Complement components C1r, C1s, C2, and complementfactors B, D and I; 6) Complement-activating component of RA-reactivefactor; 7) Cytotoxic cell proteases (granzymes A to H); 8) Duodenase I;9) Elastases 1, 2, 3A, 3B (protease E), leukocyte (medullasin); 10)Enterokinase (EC 3.4.21.9) (enteropeptidase); 11) Hepatocyte growthfactor activator; 12) Hepsin; 13) Glandular (tissue) kallikreins(including EGF-binding protein types A, B, and C, NGF-gamma chain,gamma-renin, prostate specific antigen (PSA) and tonin); 14) Plasmakallikrein; 15) Mast cell proteases (MCP) 1 (chymase) to 8; 16)Myeloblastin (proteinase 3) (Wegener's autoantigen); 17) Plasminogenactivators (urokinase-type, and tissue-type); 18) Trypsins I, II, III,and IV; 19) Tryptases; 20) Snake venom proteases such as ancrod,batroxobin, cerastobin, flavoxobin, and protein C activator; 21)Collagenase from common cattle grub and collagenolytic protease fromAtlantic sand fiddler crab; 22) Apolipoprotein(a); 23) Blood flukecercarial protease; 24) Drosophila trypsin like proteases: alpha,easter, snake-locus; 25) Drosophila protease stubble (gene sb); and 26)Major mite fecal allergen Der p III. All the above proteins belong tofamily S1 in the classification of peptidases (Rawlings N. D., et al.,Meth. Enzymol. (1994) 244:19) and originate from eukaryotic species. Itshould be noted that bacterial proteases that belong to family S2A aresimilar enough in the regions of the active site residues that they canbe picked up by the same patterns.

ff) WD Domain, G-Beta Repeats (WD_domain). A few of the validationsequences, and the sequences they validate, represent novel members ofthe WD domain/G-beta repeat family. Beta-transducin (G-beta) is one ofthe three subunits (alpha, beta, and gamma) of the guaninenucleotide-binding proteins (G proteins) which act as intermediaries inthe transduction of signals generated by transmembrane receptors(Gilman, Annu. Rev. Biochem. (1987) 56:615). The alpha subunit binds toand hydrolyzes GTP; the functions of the beta and gamma subunits areless clear but they seem to be required for the replacement of GDP byGTP as well as for membrane anchoring and receptor recognition.

In higher eukaryotes, G-beta exists as a small multigene family ofhighly conserved proteins of about 340 amino acid residues.Structurally, G-beta consists of eight tandem repeats of about 40residues, each containing a central Trp-Asp motif (this type of repeatis sometimes called a WD-40 repeat). Such a repetitive segment has beenshown to exist in a number of other proteins including: human LIS1, aneuronal protein involved in type-i lissencephaly; and mammaliancoatomer beta′ subunit (beta′-COP), a component of a cytosolic proteincomplex that reversibly associates with Golgi membranes to form vesiclesthat mediate biosynthetic protein transport.

gg) wnt Family of Developmental Signaling Proteins (Wnt_dev_sign).Several of the validation sequences, and thus the sequences theyvalidate, correspond to novel members of the wnt family of developmentalsignaling proteins. Wnt-1 (previously known as int-1), the seminalmember of this family, (Nusse R., Trends Genet. (1988) 4:291) is aproto-oncogene induced by the integration of the mouse mammary tumorvirus. It is thought to play a role in intercellular communication andseems to be a signalling molecule important in the development of thecentral nervous system (CNS). The sequence of wnt-1 is highly conservedin mammals, fish, and amphibians. Wnt-1 was found to be a member of alarge family of related proteins (Nusse R., et al., Cell (1992) 69:1073;McMahon A. P., Trends Genet. (1992) 8:1; Moon R. T., BioEssays (1993)15:91) that are all thought to be developmental regulators. Theseproteins are known as wnt-2 (also known as irp), wnt-3, -3A, -4, -5A,-5B, -6, -7A, -7B, -8, -8B, -9 and -10. At least four members of thisfamily are present in Drosophila; one of them, wingless (wg), isimplicated in segmentation polarity.

All these proteins share the following features characteristics ofsecretory proteins: a signal peptide, several potential N-glycosylationsites and 22 conserved cysteines that are probably involved in disulfidebonds. The Wnt proteins seem to adhere to the plasma membrane of thesecreting cells and are therefore likely to signal over only few celldiameters. All sequences known to belong to this family are detected bythe provided consensus pattern.

hh) Protein Tyrosine Phosphatase (Y_phosphatase). Several of thevalidation sequences, and thus the sequences they validate, represent apolynucleotide encoding a protein tyrosine kinase. Tyrosine specificprotein phosphatases (EC 3.1.3.48) (PTPase) (Fischer et al., Science(1991) 253:401; Charbonneau et al., Annu. Rev. Cell Biol. (1992) 8:463;Trowbridge, J. Biol. Chem. (1991) 266:23517; Tonks et al., TrendsBiochem. Sci. (1989) 14:497; and Hunter, Cell (1989) 58:1013) catalyzethe removal of a phosphate group attached to a tyrosine residue. Theseenzymes are very important in the control of cell growth, proliferation,differentiation and transformation. Multiple forms of PTPase have beencharacterized and can be classified into two categories: soluble PTPasesand transmembrane receptor proteins that contain PTPase domain(s).

Soluble PTPases include PTPN3 (H1) and PTPN4 (MEG), enzymes that containan N-terminal band 4.1-like domain and could act at junctions betweenthe membrane and cytoskeleton; PTPN6 (PTP-1C; HCP; SHP) and PTPN11(PTP-2C; SH-PTP3; Syp), enzymes that contain two copies of the SH2domain at its N-terminal extremity.

Dual specificity PTPases include DUSP1 (PTPN10; MAP kinasephosphatase-1; MKP-1) which dephosphorylates MAP kinase on both Thr-183and Tyr-185; and DUSP2 (PAC-1), a nuclear enzyme that dephosphorylatesMAP kinases ERK1 and ERK2 on both Thr and Tyr residues.

Structurally, all known receptor PTPases are made up of a variablelength extracellular domain, followed by a transmembrane region and aC-terminal catalytic cytoplasmic domain. Some of the receptor PTPasescontain fibronectin type III (FN-III) repeats, immunoglobulin-likedomains, MAM domains or carbonic anhydrase-like domains in theirextracellular region. The cytoplasmic region generally contains twocopies of the PTPAse domain. The first seems to have enzymatic activity,while the second is inactive but seems to affect substrate specificityof the first. In these domains, the catalytic cysteine is generallyconserved but some other, presumably important, residues are not.

PTPase domains consist of about 300 amino acids. There are two conservedcysteines and the second one has been shown to be absolutely requiredfor activity. Furthermore, a number of conserved residues in itsimmediate vicinity have also been shown to be important.

ii) Zinc Finger, C2H2 Type (Zincfing_C2H2). Several of the validationsequences, and thus the sequences they validate, correspond topolynucleotides encoding novel members of the of the C2H2 type zincfinger protein family. Zinc finger domains (Klug et al., Trends Biochem.Sci. (1987) 12:464; Evans et al., Cell (1988) 52:1; Payre et al., FEBSLett. (1988) 234:245; Miller et al., EMBO J. (1985) 4:1609; and Berg,Proc. Natl. Acad. Sci. USA (1988) 85:99) are nucleic acid-bindingprotein structures first identified in the Xenopus transcription factorTFIIIA. These domains have since been found in numerous nucleicacid-binding proteins. A zinc finger domain is composed of 25 to 30amino acid residues. Two cysteine or histidine residues are positionedat both extremities of the domain, which are involved in the tetrahedralcoordination of a zinc atom. It has been proposed that such a domaininteracts with about five nucleotides.

Many classes of zinc fingers are characterized according to the numberand positions of the histidine and cysteine residues involved in thezinc atom coordination. In the first class to be characterized, calledC2H2, the first pair of zinc coordinating residues are cysteines, whilethe second pair are histidines. A number of experimental reports havedemonstrated the zinc-dependent DNA or RNA binding property of somemembers of this class.

Mammalian proteins having a C2H2 zipper include (number in parenthesisindicates number of zinc finger regions in the protein): basonuclin (6),BCL-6/LAZ-3 (6), erythroid krueppel-like transcription factor (3),transcription factors Sp1 (3), Sp2 (3), Sp3 (3) and Sp(4) 3,transcriptional repressor YY1 (4), Wilms' tumor protein (4), EGR1/Krox24(3), EGR2/Krox20 (3), EGR3/Pilot (3), EGR4/AT133 (4), Evi-1 (10), GLI1(5), GLI2 (4+), GLI3 (3+), HIV-EP1/ZNF40 (4), HIV-EP2 (2), KR1 (9+), KR2(9), KR3 (15+), KR4 (14+), KR5 (11+), HF.12 (6+), REX-1 (4), ZfX (13),ZfY (13), Zfp-35 (18), ZNF7 (15), ZNF8 (7), ZNF35 (10), ZNF42/MZF-1(13), ZNF43 (22), ZNF46/Kup (2), ZNF76 (7), ZNF91 (36), ZNF133 (3).

In addition to the conserved zinc ligand residues, it has been shownthat a number of other positions are also important for the structuralintegrity of the C2H2 zinc fingers. (Rosenfeld et al., J. Biomol.Struct. Dyn. (1993) 11:557) The best conserved position is found fourresidues after the second cysteine; it is generally an aromatic oraliphatic residue. The consensus pattern for C2H2 zinc fingers is:C-x(2,4)-C-x(3)-[LIVMFYWC]-x(8)-H-x(3,5)-H. The two C's and two H's arezinc ligands.

jj) Zinc finger C3HC4 type (RING finger), signature (Zincfing_C3H4).Some SEQ ID NOS, and thus the sequences they validate, representpolynucleotides encoding a polypeptide having a C3HC4 type zinc fingersignature. A number of eukaryotic and viral proteins contain thissignature, which is primarily a conserved cysteine-rich domain of 40 to60 residues (Borden K. L. B., et al., Curr. Opin. Struct. Biol. (1996)6:395) that binds two atoms of zinc, and is probably involved inmediating protein-protein interactions. The 3D structure of the zincligation system is unique to the RING domain and is refered to as the“cross-brace” motif.

1) Mammalian V(D)J recombination activating protein (RAG1). RAG1activates the rearrangement of immunoglobulin and T-cell receptor genes.

2) Mouse rpt-1. Rpt-1 is a trans-acting factor that regulates geneexpression directed by the promoter region of the interleukin-2 receptoralpha chain or the LTR promoter region of HIV-1.

3) Human rip. Rfp is a developmentally regulated protein that mayfunction in male germ cell development. Recombination of the N-terminalsection of rfp with a protein tyrosine kinase produces the rettransforming protein.

4) Human 52 Kd Ro/SS-A protein. A protein of unknown function from theRo/SS-A ribonucleoprotein complex. Sera from patients with systemiclupus erythematosus or primary Sjogren's syndrome often containantibodies that react with the Ro proteins.

5) Human histocompatibility locus protein RING1.

6) Human PML, a probable transcription factor. Chromosomal translocationof PML with retinoic receptor alpha creates a fusion protein which isthe cause of acute promyelocytic leukemia (APL).

7) Mammalian breast cancer type 1 susceptibility protein (BRCA1) ([E1]http://bioinformatics.weizmann.ac.il/hotmolecbase/entries/brca1.htm).

8) Mammalian cbl proto-oncogene.

9) Mammalian bmi-1 proto-oncogene.

10) Vertebrate CDK-activating kinase (CAK) assembly factor MAT I, aprotein that stabilizes the complex between the CDK7 kinase and cyclin H(MAT1 stands for ‘Menage A Trois’).

11) Mammalian mel-18 protein. Mel-18 which is expressed in a variety oftumor cells is a transcriptional repressor that recognizes and bind aspecific DNA sequence.

12) Mammalian peroxisome assembly factor-1 (PAF-1) (PMP35), which issomewhat involved in the biogenesis of peroxisomes. In humans, defectsin PAF-1 are responsible for a form of Zellweger syndrome, an autosomalrecessive disorder associated with peroxisomal deficiencies.

13) Human MAT1 protein, which interacts with the CDK7-cyclin H complex.

14) Human RING1 protein.

15) Xenopus XNF7 protein, a probable transcription factor.

16) Trypanosoma protein ESAG-8 (T-LR), which may be involved in thepostranscriptional regulation of genes in VSG expression sites or mayinteract with adenylate cyclase to regulate its activity.

17) Drosophila proteins Posterior Sex Combs (Psc) and Suppressor two ofzeste (Su(z)₂). The two proteins belong to the Polycomb group of genesneeded to maintain the segment-specific repression of homeotic selectorgenes.

18) Drosophila protein male-specific msl-2, a DNA-binding protein whichis involved in X chromosome dosage compensation (the elevation oftranscription of the male single X chromosome).

19) Arabidopsis thaliana protein COP1 which is involved in theregulation of photomorphogenesis.

20) Fungal DNA repair proteins RAD5, RAD16, RAD 18 and rad8.

21) Herpesviruses trans-acting transcriptional protein ICP0/IE110. Thisprotein which has been characterized in many different herpesviruses isa trans-activator and/or -repressor of the expression of many viral andcellular promoters.

22) Baculoviruses protein CG30.

23) Baculoviruses major immediate early protein (PE-38).

24) Baculoviruses immediate-early regulatory protein IE-N/IE-2.

25) Caenorhabditis elegans hypothetical proteins F54G8.4, R05D3.4 andT02C1.1.

26) Yeast hypothetical proteins YER116c and YKR017c.

The signature pattern for the C3HC4 finger is based on the centralregion of the domain:

Example 17 Differential Expression of Polynucleotides of the Invention:Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the inventionwas assessed in several libraries prepared from various sources,including cell lines and patient tissue samples. Table 20 provides asummary of these libraries, including the shortened library name (usedhereafter), the mRNA source used to prepared the cDNA library, the“nickname” of the library that is used in the tables below (in quotes),and the approximate number of clones in the library. TABLE 20Description of cDNA Libraries Number of Library Clones in this (lib #)Description Clustering 1 Km12 L4 307133 Human Colon Cell Line, HighMetastatic Potential (derived from Km12C) “High Colon” 2 Km12C 284755Human Colon Cell Line, Low Metastatic Potential “Low Colon” 3 MDA-MB-231326937 Human Breast Cancer Cell Line, High Metastatic Potential; micro-metastases in lung “High Breast” 4 MCF7 318979 Human Breast Cancer Cell,Non Metastatic “Low Breast” 8 MV-522 223620 Human Lung Cancer Cell Line,High Metastatic Potential “High Lung” 9 UCP-3 312503 Human Lung CancerCell Line, Low Metastatic Potential “Low Lung” 12 Human microvascularendothelial cells (HMEC) - Untreated 41938 PCR (OligodT) cDNA library 13Human microvascular endothelial cells (HMEC) - Basic fibroblast 42100growth factor (bFGF) treated PCR (OligodT) cDNA library 14 Humanmicrovascular endothelial cells (HMEC) - Vascular endothelial 42825growth factor (VEGF) treated PCR (OligodT) cDNA library 15 NormalColon - UC#2 Patient 34285 PCR (OligodT) cDNA library “Normal ColonTumor Tissue” 16 Colon Tumor - UC#2 Patient 35625 PCR (OligodT) cDNAlibrary “Normal Colon Tumor Tissue” 17 Liver Metastasis from Colon Tumorof UC#2 Patient 36984 PCR (OligodT) cDNA library “High Colon MetastasisTissue” 18 Normal Colon - UC#3 Patient 36216 PCR (OligodT) cDNA library“Normal Colon Tumor Tissue” 19 Colon Tumor - UC#3 Patient 41388 PCR(OligodT) cDNA library “High Colon Tumor Tissue” 20 Liver Metastasisfrom Colon Tumor of UC#3 Patient 30956 PCR (OligodT) cDNA library “HighColon Metastasis Tissue”

The KM12L4 and KM12C cell lines are described in Example 14 above. TheMDA-MB-231 cell line was originally isolated from pleural effusions(Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastaticpotential, and forms poorly differentiated adenocarcinoma grade II innude mice consistent with breast carcinoma. The MCF7 cell line wasderived from a pleural effusion of a breast adenocarcinoma and isnon-metastatic. The MV-522 cell line is derived from a human lungcarcinoma and is of high metastatic potential. The UCP-3 cell line is alow metastatic human lung carcinoma cell line; the MV-522 is a highmetastatic variant of UCP-3. These cell lines are well-recognized in theart as models for the study of human breast and lung cancer (see, e.g.,Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7);Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ransonet al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al.,Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al.,Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990)11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637;(MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); andZhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples oflibraries 15-20 are derived from two different patients (UC#2, andUC#3). The bFGF-treated HMEC were prepared by incubation with bFGF at 10ng/ml for 2 hrs; the VEGF-treated HMEC were prepared by incubation with20 ng/ml BEGF for 2 hrs. Following incubation with the respective growthfactor, the cells were washed and lysis buffer added for RNApreparation.

Each of the libraries is composed of a collection of cDNA clones that inturn are representative of the mRNAs expressed in the indicated mRNAsource. In order to facilitate the analysis of the millions of sequencesin each library, the sequences were assigned to clusters. The concept of“cluster of clones” is derived from a sorting/grouping of cDNA clonesbased on their hybridization pattern to a panel of roughly 300 7 bpoligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29).Random cDNA clones from a tissue library are hybridized at moderatestringency to 300 7 bp oligonucleotides. Each oligonucleotide has somemeasure of specific hybridization to that specific clone. Thecombination of 300 of these measures of hybridization for 300 probesequals the “hybridization signature” for a specific clone. Clones withsimilar sequence will have similar hybridization signatures. Bydeveloping a sorting/grouping algorithm to analyze these signatures,groups of clones in a library can be identified and brought togethercomputationally. These groups of clones are termed “clusters”. Dependingon the stringency of the selection in the algorithm (similar to thestringency of hybridization in a classic library cDNA screeningprotocol), the “purity” of each cluster can be controlled. For example,artifacts of clustering may occur in computational clustering just asartifacts can occur in “wet-lab” screening of a cDNA library with 400 bpcDNA fragments, at even the highest stringency. The stringency used inthe implementation of cluster herein provides groups of clones that arein general from the same cDNA or closely related cDNAs. Closely relatedclones can be a result of different length clones of the same cDNA,closely related clones from highly related gene families, or splicevariants of the same cDNA.

Differential expression for a selected cluster was assessed by firstdetermining the number of cDNA clones corresponding to the selectedcluster in the first library (Clones in 1^(st)), and the determining thenumber of cDNA clones corresponding to the selected cluster in thesecond library (Clones in 2^(nd)). Differential expression of theselected cluster in the first library relative to the second library isexpressed as a “ratio” of percent expression between the two libraries.In general, the “ratio” is calculated by: 1) calculating the percentexpression of the selected cluster in the first library by dividing thenumber of clones corresponding to a selected cluster in the firstlibrary by the total number of clones analyzed from the first library;2) calculating the percent expression of the selected cluster in thesecond library by dividing the number of clones corresponding to aselected cluster in a second library by the total number of clonesanalyzed from the second library; 3) dividing the calculated percentexpression from the first library by the calculated percent expressionfrom the second library. If the “number of clones” corresponding to aselected cluster in a library is zero, the value is set at 1 to aid incalculation. The formula used in calculating the ratio takes intoaccount the “depth” of each of the libraries being compared, i.e., thetotal number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentiallyexpressed between two samples when the ratio value is greater than atleast about 2, preferably greater than at least about 3, more preferablygreater than at least about 5, where the ratio value is calculated usingthe method described above. The significance of differential expressionis determined using a z score test (Zar, Biostatistical Analysis,Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298(1974).

Example 18 Polynucleotides Differentially Expressed in High MetastaticPotential Breast Cancer Cells Versus Low Metastatic Breast Cancer Cells

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential breast cancer tissue and low metastatic breast cancer cells.Expression of these sequences in breast cancer can be valuable indetermining diagnostic, prognostic and/or treatment information. Forexample, sequences that are highly expressed in the high metastaticpotential cells can be indicative of increased expression of genes orregulatory sequences involved in the metastatic process. A patientsample displaying an increased level of one or more of thesepolynucleotides may thus warrant more aggressive treatment. In anotherexample, sequences that display higher expression in the low metastaticpotential cells can be associated with genes or regulatory sequencesthat inhibit metastasis, and thus the expression of thesepolynucleotides in a sample may warrant a more positive prognosis thanthe gross pathology would suggest.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic marker, for risk assessment, patienttreatment and the like. These polynucleotide sequences can also be usedin combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentiallyexpressed between high metastatic potential breast cancer cells and lowmetastatic potential breast cancer cells. TABLE 21 Differentiallyexpressed polynucleotides: Higher expression in high metastaticpotential breast cancer (lib3) relative to low metastatic breast cancercells (lib4) SEQ ID Cluster Lib3 Lib4 NOS: Sequence Name ID clonesclones lib3/lib4 Zscore 889 RTA00000197AR.f.12.1 3513 17 5 3.3172402.287632 990 RTA00000185AF.a.19.2 5749 9 0 8.780930 2.629923 998RTA00000196F.e.7.1 1039 10 2 4.878294 1.978215 1003 RTA00000182AF.1.12.11027 41 17 2.353059 2.926571 1009 RTA00000192AF.g.23.1 6455 6 0 5.8539532.011224 1018 RTA00000181AF.e.22.3 3442 17 4 4.146550 2.562391 1027RTA00000198AF.c.17.1 6923 6 0 5.853953 2.011224 1208RTA00000187AF.g.13.1 2991 10 1 9.756589 2.371428 1210RTA00000192AF.o.19.1 3549 10 1 9.756589 2.371428 1231RTA00000191AF.j.14.1 1002 42 20 2.048883 2.570309 1340RTA00000190AF.p.3.1 2378 34 0 33.17240 5.588184 1354RTA00000178AF.n.23.1 3298 12 1 11.70790 2.729313 1356RTA00000191AF.c.3.1 3549 10 1 9.756589 2.371428 1373RTA00000178AF.b.13.1 3114 9 1 8.780930 2.174815 1404RTA00000184AF.i.23.3 1577 25 3 8.130490 3.903813 1450RTA00000179AR.e.01.4 2493 33 9 3.577416 3.469507 1488RTA00000197F.i.12.1 3605 14 1 13.65922 3.050936 1490RTA00000186AF.d.24.1 3114 9 1 8.780930 2.174815 1598RTA00000187AF.1.11.1 4482 14 3 4.553074 2.374769 1719RTA00000401F.m.02.1 1573 34 7 4.738914 3.982056 1746 RTA00000422F.c.02.12902 18 5 3.512372 2.443314 1765 RTA00000418F.m.19.1 8890 6 0 5.8539532.011224 1786 RTA00000351R.g.11.1 3077 17 4 4.146550 2.562391 1939RTA00000408F.1.13.1 4423 12 1 11.70790 2.729313 1948 RTA00000404F.m.10.2779 60 22 2.660887 3.974953 1975 RTA00000400F.k.22.1 2512 7 0 6.8296122.235371 2014 RTA00000340R.f.05.1 3202 18 3 5.853953 2.998867 2028RTA00000422F.c.17.1 1360 26 11 2.306102 2.226876 2049RTA00000118A.a.23.1 3500 12 3 3.902635 2.018050 2198 RTA00000401F.k.14.1211 121 43 2.745458 5.856098 2968 RTA00000191AF.j.14.1 1002 42 202.048883 2.570309 2379 RTA00000405F.l.11.1 2055 29 8 3.536763 3.2133732595 RTA00000423F.j.03.1 5391 6 0 5.853953 2.011224 2608RTA00000399F.o.24.1 2272 17 1 16.58620 3.483575 2621 RTA00000401F.j.15.13061 14 0 13.65922 3.428594 2639 RTA00000348R.o.12.1 2263 6 0 5.8539532.011224 2713 RTA00000340F.f.22.1 1720 57 8 6.951569 5.855075 2726RTA00000401F.g.22.1 1147 28 12 2.276537 2.294031 2734RTA00000346F.o.16.1 176 170 44 3.769591 8.366611 2759RTA00000400F.g.02.1 1508 21 5 4.097767 2.879196 2884 RTA00000527F.j.02.24896 11 0 10.73224 2.974502 2903 RTA00000528F.i.22.1 2478 17 5 3.3172402.287632 3067 RTA00000528F.j.11.1 1070 26 6 4.227855 3.289393 3089RTA00000527F.k.09.1 213 17 4 4.146550 2.562391 3144 RTA00000528F.b.03.12078 11 2 5.366124 2.174565 3169 RTA00000525F.d.13.1 349 77 1 75.125738.384408 3306 RTA00000528F.g.22.2 920 76 32 2.317189 4.010278 3332RTA00000528F.h.02.2 1701 18 4 4.390465 2.714073 3336 RTA00000528F.c.11.11701 18 4 4.390465 2.714073

TABLE 22 Differentially expressed polynucleotides: Higher expression inlow metastatic breast cancer cells (lib4) relative to high metastaticpotential breast cancer (lib3) SEQ ID Lib4 Lib 3 NOS: Sequence NameCluster ID Clones Clones lib4/lib3 Zscore 859 RTA00000177AR.n.8.1 4188 413 3.33108 1.99126 880 RTA00000181AF.p.4.3 40392 1 8 8.19958 2.03713 888RTA00000199F.f.08.2 12445 0 11 11.2744 3.05623 933 RTA00000177AF.n.8.34188 4 13 3.33108 1.99126 1016 RTA00000186AF.p.09.2 6879 3 43 14.69095.83444 1047 RTA00000201F.d.09.1 1827 37 157 4.34910 8.71727 1105RTA00000192AF.a.24.1 13183 0 7 7.17463 2.30057 1263 RTA00000182AF.j.20.14769 2 20 10.2494 3.68254 1264 RTA00000181AF.c.11.1 4769 2 20 10.24943.68254 1347 RTA00000197AF.k.9.1 3138 1 10 10.2494 2.45316 1396RTA00000193AF.b.24.1 35 386 1967 5.22298 33.2328 1408RTA00000200AF.g.18.1 1600 0 23 23.5738 4.64683 1414 RTA00000183AF.a.19.23788 0 6 6.14969 2.07158 1434 RTA00000190AF.d.2.1 2444 26 55 2.168153.22244 1537 RTA00000198F.m.12.1 4 987 2807 2.91492 30.3819 1551RTA00000179AF.p.15.1 5622 2 13 6.66216 2.62993 1555 RTA00000198F.i.2.18076 0 9 9.22453 2.70385 1570 RTA00000200R.f.10.1 4 987 2807 2.9149230.3819 1590 RTA00000178AF.i.01.2 4 987 2807 2.91492 30.3819 1600RTA00000404F.a.02.1 9738 1 13 13.3243 2.98623 1834 RTA00000126A.o.23.16268 3 18 6.14969 3.11179 1966 RTA00000401F.o.06.1 2679 4 23 5.893453.52846 1986 RTA00000411F.a.15.1 73812 0 12 12.2993 3.21838 2130RTA00000345F.n.12.1 7337 3 16 5.46639 2.80694 2133 RTA00000126A.g.7.11902 13 48 3.78442 4.45002 2279 RTA00000345F.e.11.1 4392 1 8 8.199582.03713 2704 RTA00000340F.p.18.1 287 6 173 29.5526 12.5749 2777RTA00000400F.f.11.1 4088 0 82 84.0457 9.05778 2778 RTA00000341F.o.12.12883 9 21 2.39154 2.07600 2823 RTA00000122A.h.24.1 48 412 1020 2.5374916.5262 2824 RTA00000346F.j.13.1 5337 5 17 3.48482 2.40321 2851RTA00000400F.g.08.1 1275 15 32 2.18655 2.41857 2867 RTA00000523F.d.19.126489 1 8 8.19958 2.03713 3253 RTA00000526F.d.17.1 2757 4 16 4.099792.51500 2064 RTA00000528F.d.04.1 2395 12 37 3.16025 3.51521

Example 19 Polynucleotides Differentially Expressed in High MetastaticPotential Lung Cancer Cells Versus Low Metastatic Lung Cancer Cells

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential lung cancer tissue and low metastatic lung cancer cells.Expression of these sequences in lung cancer tissue can be valuable indetermining diagnostic, prognostic and/or treatment information. Forexample, sequences that are highly expressed in the high metastaticpotential cells are associated can be indicative of increased expressionof genes or regulatory sequences involved in the metastatic process. Apatient sample displaying an increased level of one or more of thesepolynucleotides may thus warrant more aggressive treatment. In anotherexample, sequences that display higher expression in the low metastaticpotential cells can be associated with genes or regulatory sequencesthat inhibit metastasis, and thus the expression of thesepolynucleotides in a sample may warrant a more positive prognosis thanthe gross pathology would suggest.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic marker, for risk assessment, patienttreatment and the like. These polynucleotide sequences can also be usedin combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentiallyexpressed between high metastatic potential lung cancer cells and lowmetastatic potential lung cancer cells: TABLE 23 Differentiallyexpressed polynucleotides: Higher expression in high metastaticpotential lung cancer cells (lib8) relative to low metastatic lungcancer cells (lib9) SEQ ID Lib8 Lib9 NO: Sequence Name Cluster ID clonesclones lib8/lib9 Zscore 854 RTA00000198AF.n.16.1 3721 9 0 12.57723.20845 898 RTA00000200F.o.22.1 983 8 1 11.1797 2.53243 909RTA00000198AF.m.16.1 51 348 66 7.36849 17.4315 1015 RTA00000198R.c.07.119181 6 0 8.38484 2.48169 1047 RTA00000201F.d.09.1 1827 45 15 4.192425.09891 1096 RTA00000181AF.e.18.3 8 1355 122 15.5211 39.0214 1097RTA00000181AF.e.17.3 8 1355 122 15.5211 39.0214 1129RTA00000181AR.j.14.3 5399 12 0 16.7696 3.80239 1263 RTA00000182AF.j.20.14769 10 3 4.65824 2.29362 1264 RTA00000181AF.c.11.1 4769 10 3 4.658242.29362 1335 RTA00000196F.k.11.1 3 986 392 3.51507 22.4683 1369RTA00000198AF.c.7.1 19181 6 0 8.38484 2.48169 1370 RTA00000185AF.e.20.15865 12 0 16.7696 3.80239 1396 RTA00000193AF.b.24.1 35 868 11 110.27334.2897 1537 RTA00000198F.m.12.1 4 506 209 3.38335 15.7309 1544RTA00000183AF.i.18.2 40129 7 0 9.78231 2.74441 1570 RTA00000200R.f.10.14 506 209 3.38335 15.7309 1586 RTA00000177AF.m.1.1 14929 23 16 2.008862.02420 1590 RTA00000178AF.i.01.2 4 506 209 3.38335 15.7309 1705RTA00000339F.f.11.1 5832 5 0 6.98736 2.18988 1834 RTA00000126A.o.23.16268 5 0 6.98736 2.18988 1932 RTA00000399F.f.11.1 40167 8 0 11.17972.98512 2132 RTA00000423F.e.11.1 2566 11 2 7.68610 2.85611 2261RTA00000339F.o.07.1 2566 11 2 7.68610 2.85611 2288 RTA00000419F.p.03.11937 10 3 4.65824 2.29362 2298 RTA00000340F.1.05.1 38935 7 0 9.782312.74441 2414 RTA00000403F.a.17.1 13686 8 0 11.1797 2.98512 2441RTA00000401F.n.23.1 1552 8 1 11.1797 2.53243 2823 RTA00000122A.h.24.1 48342 155 3.08345 12.2138 2868 RTA00000528F.b.23.1 1605 22 4 7.686104.23808 2878 RTA00000528F.m.16.1 4468 6 1 8.38484 1.97787 2970RTA00000526F.d.01.1 4468 6 1 8.38484 1.97787

TABLE 24 Differentially expressed polynucleotides: Higher expression inlow metastatic lung cancer cells (lib9) relative to high metastaticpotntial lung cancer cells SEQ ID Cluster Lib8 Lib9 NO: Sequence Name IDclones clones lib9/lib8 Zscore 1018 RTA00000181AF.e.22.3 3442 5 233.291654 2.368262 1098 RTA00000178AF.n.2.1 17083 0 8 5.724617 2.0341171310 RTA00000177AF.p.20.1 4141 4 27 4.830145 3.070829 1415RTA00000198AF.b.14.1 801 16 46 2.057284 2.411087 1418RTA00000192AF.f.3.1 5257 5 25 3.577885 2.596857 1434 RTA00000190AF.d.2.12444 12 37 2.206362 2.299984 1766 RTA00000399F.1.14.1 3354 5 20 2.8623081.998763 2199 RTA00000406F.m.04.1 14959 11 41 2.667151 2.865855 2266RTA00000405F.h.07.2 4984 3 16 3.816411 2.058861 2851 RTA00000400F.g.08.11275 10 42 3.005423 3.147111 2882 RTA00000527F.p.06.1 1292 8 33 2.9517552.724411 3089 RTA00000527F.k.09.1 213 137 403 2.104945 7.661033

Example 20 Polynucleotides Differentially Expressed in High MetastaticPotential Colon Cancer Cells Versus Low Metastatic Colon Cancer Cells

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential colon cancer tissue and low metastatic colon cancer cells.Expression of these sequences in colon cancer tissue can be valuable indetermining diagnostic, prognostic and/or treatment information. Forexample, sequences that are highly expressed in the high metastaticpotential cells can be indicative of increased expression of genes orregulatory sequences involved in the metastatic process. A patientsample displaying an increased level of one or more of thesepolynucleotides may thus warrant more aggressive treatment. In anotherexample, sequences that display higher expression in the low metastaticpotential cells can be associated with genes or regulatory sequencesthat inhibit metastasis, and thus the expression of thesepolynucleotides in a sample may warrant a more positive prognosis thanthe gross pathology would suggest.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic marker, for risk assessment, patienttreatment and the like. These polynucleotide sequences can also be usedin combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides withdifferential expression between high metastatic potential colon cancercells and low metastatic potential colon cancer cells: TABLE 25Differentially expressed polynucleotides: Higher expression in highmetastatic potential colon cancer (lib1) relative to low metastaticcolon cancer cells (lib2) SEQ ID Lib1 Lib2 NO: Sequence Name Cluster IDclones clones lib1/lib2 Zscore 1072 RTA00000187AR.h.15.2 6660 7 06.489973399 2.169320547 1124 RTA00000193AF.b.18.1 7542 8 0 7.4171124562.36964728 1199 RTA00000184AR.b.24.1 5777 9 1 8.344251513 2.095551461335 RTA00000196F.k.11.1 3 5268 2164 2.257009497 32.96556438 1447RTA00000183AR.d.11.3 6420 8 0 7.417112456 2.36964728 1524RTA00000177AF.f.10.1 6420 8 0 7.417112456 2.36964728 1596RTA00000192AF.o.7.1 5275 11 2 5.099264814 2.083995588 1597RTA00000192AF.o.17.1 5275 11 2 5.099264814 2.083995588 2085RTA00000346F.1.13.1 7542 8 0 7.417112456 2.36964728 2108RTA00000349R.g.10.1 5777 9 1 8.344251513 2.09555146 2245RTA00000421F.m.14.1 3524 21 6 3.2449867 2.499690198 2286RTA00000350R.g.10.1 9026 7 0 6.489973399 2.169320547 2358RTA00000399F.o.06.1 13574 7 0 6.489973399 2.169320547 2695RTA00000421F.a.06.1 2385 27 4 6.258188635 3.743586088 2759RTA00000400F.g.02.1 1508 46 17 2.508729213 3.230059264 2868RTA00000528F.b.23.1 1605 36 11 3.034273278 3.244010467 2910RTA00000528F.m.12.1 5768 12 0 3.046665462

TABLE 26 Differentially expressed polynucleotides: Higher expression inlow metastatic colon cancer cells (lib2)relative to high metastaticpotential colon cancer (lib1) SEQ ID Cluster Lib2 NOS: Sequence Name IDLib1 clones clones lib2/lib1 Zscore 877 RTA00000178AR.a.20.1 945 9 212.51670 2.21703 1094 RTA00000192AF.j.21.1 2289 3 23 8.26916 3.92187 1126RTA00000193AF.c.15.1 3726 3 14 5.03340 2.58312 1214 RTA00000179AF.c.15.32995 4 13 3.50540 2.09770 1231 RTA00000191AF.j.14.1 1002 12 65 5.842346.26259 1287 RTA00000197AR.i.17.1 3516 5 17 3.66719 2.52439 1304RTA00000179AF.c.15.1 2995 4 13 3.50540 2.09770 1389 RTA00000196F.a.2.13575 5 14 3.02004 2.00158 1404 RTA00000184AF.i.23.3 1577 12 40 3.595284.01991 1547 RTA00000198F.1.09.1 3611 2 13 7.01081 2.73040 1548RTA00000190AF.o.12.1 3438 5 14 3.02004 2.00158 1939 RTA00000408F.1.13.14423 1 8 8.62869 2.11495 1948 RTA00000404F.m.10.2 779 27 54 2.157173.23169 2049 RTA00000118A.a.23.1 3500 3 13 4.67387 2.40298 2198RTA00000401F.k.14.1 211 109 206 2.03843 6.08597 2231RTA00000191AF.j.14.1 1002 12 65 5.84234 6.26259 2578 RTA00000345F.b.17.1945 9 21 2.51670 2.21703 2586 RTA00000422F.b.22.1 2368 14 34 2.619423.00662 2798 RTA00000401F.j.23.1 570 59 148 2.70560 6.66631 3106RTA00000527F.o.12.1 688 29 60 2.23155 3.53946 3169 RTA00000525F.d.13.1349 69 138 2.15717 5.27497

Example 21 Polynucleotides Differentially Expressed in High MetastaticPotential Colon Cancer Patient Tissue Versus Normal Patient Tissue

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential colon cancer tissue and normal tissue. Expression of thesesequences in colon cancer tissue can be valuable in determiningdiagnostic, prognostic and/or treatment information. For example,sequences that are highly expressed in the high metastatic potentialcells are associated can be indicative of increased expression of genesor regulatory sequences involved in the advanced disease state whichinvolves processes such as angiogenesis, dedifferentiation, cellreplication, and metastasis. A patient sample displaying an increasedlevel of one or more of these polynucleotides may thus warrant moreaggressive treatment.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic marker, for risk assessment, patienttreatment and the like. These polynucleotide sequences can also be usedin combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentiallyexpressed between high metastatic potential colon cancer cells andnormal colon cells: TABLE 27 Differentially expressed polynucleotidesisolated from samples from two patients (UC#2 and UC#3): Higherexpression in high metastatic potential colon tissue (UC#2: lib17; UC#3:lib20) vs. normal colon tissue (UC#2: lib15; UC#3: lib18) SEQ ID Clusterlib17 NO: Sequence Name ID lib15 clones clones lib17/lib15 Zscore 909RTA00000198AF.m.16.1 51 1 10 9.27022 2.28830 2624 RTA00000118A.j.24.1 184 23 5.33037 3.27028 2743 RTA00000345F.j.09.1 13 14 80 5.29727 6.34580SEQ ID Cluster lib18 lib20 NO: Sequence Name ID clones cloneslib20/lib18 Zscore 2743 RTA00000345F.j.09.1 13 12 23 2.24234 2.16077

TABLE 28 Differentially expressed polynucleotides isolated from samplesfrom two patients (UC#2 and UC#3): Higher expression in normal colontissue (UC#2: lib15; UC#3: lib18)vs. high metastatic potential colontissue (UC#2: lib17; UC#3: lib20). SEQ ID Cluster Lib5 L1ib7 Z Score:NO: Sequence Name ID Clones Clones lib15/lib17 >2.5899%; >1.96 1335RTA00000196F.k.11.1 3 242 26 10.04 13.78900072 SEQ ID Cluster Lib18Lib20 NO: Sequence Name ID clones clones lib18/lib20 Zscore 1335RTA00000196F.k.11.1 3 409 46 7.59993 15.3998

Example 22 Polynucleotides Differentially Expressed in High Colon TumorPotential Patient Tissue Versus Metastasized Colon Cancer Patient Tissue

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high tumor potentialcolon cancer tissue and cells derived from high metastatic potentialcolon cancer cells. Expression of these sequences in colon cancer tissuecan be valuable in determining diagnostic, prognostic and/or treatmentinformation associated with the transformation of precancerous tissue tomalignant tissue. This information can be useful in the prevention ofachieving the advanced malignant state in these tissues, and can beimportant in risk assessment for a patient.

The following table summarizes identified polynucleotides withdifferential expression between high tumor potential colon cancer tissueand cells derived from high metastatic potential colon cancer cells:TABLE 29 Differentially expressed polynucleotides: High tumor potentialcolon tissue vs. metastatic colon tissue SEQ ID L19 L20 NO: SequenceName Cluster ID clones clones lib19/lib20 Zscore 1096RTA00000181AF.e.18.3 8 14 1 10.4712 2.56699 1097 RTA00000181AF.e.17.3 814 1 10.4712 2.56699 1335 RTA00000196F.k.11.1 3 328 46 5.33318 11.89621425 RTA00000191AF.p.3.2 17 24 2 8.97535 3.41950 1537RTA00000198F.m.12.1 4 26 8 2.43082 2.09705 1570 RTA00000200R.f.10.1 4 268 2.43082 2.09705 1590 RTA00000178AF.i.01.2 4 26 8 2.43082 2.09705 2624RTA00000118A.j.24.1 18 80 13 4.60274 5.51440 2743 RTA00000345F.j.09.1 13148 23 4.81287 7.68618

Example 23 Polynucleotides Differentially Expressed in High TumorPotential Colon Cancer Patient Tissue Versus Normal Patient Tissue

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high tumor potentialcolon cancer tissue and normal tissue. Expression of these sequences incolon cancer tissue can be valuable in determining diagnostic,prognostic and/or treatment information associated with the preventionof achieving the malignant state in these tissues, and can be importantin risk assessment for a patient. For example, sequences that are highlyexpressed in the potential colon cancer cells are associated with or canbe indicative of increased expression of genes or regulatory sequencesinvolved in early tumor progression. A patient sample displaying anincreased level of one or more of these polynucleotides may thus warrantcloser attention or more frequent screening procedures to catch themalignant state as early as possible.

The following tables summarize polynucleotides that are differentiallyexpressed between high metastatic potential colon cancer cells andnormal colon cells: TABLE 30 Differentially expressed polynucleotidesdetected in samples from two patients (UC#2 and UC#3): Higher expressionin tumor potential colon tissue (UC#2: lib16; UC#3: lib19)vs. normalcolon tissue (UC#2: lib15; UC#3: lib18) SEQ ID Lib15 Lib16 NO: SequenceName Cluster ID clones clones lib16/lib15 Zscore 2743RTA00000345F.j.09.1 13 14 50 3.43709 4.22436 SEQ ID Cluster Lib18 Lib19NO: Sequence Name ID clones clones lib19/lib18 Zscore 909RTA00000198AF.m.16.1 51 0 14 12.2505 3.23250 1096 RTA00000181AF.e.18.3 81 14 12.2505 2.84687 1097 RTA00000181AF.e.17.3 8 1 14 12.2505 2.846871425 RTA00000191AF.p.3.2 17 4 24 5.25021 3.24580 1537RTA00000198F.m.12.1 4 6 26 3.79182 2.98901 1560 RTA00000200F.p.05.1 39840 7 6.12525 2.09621 1570 RTA00000200R.f.10.1 4 6 26 3.79182 2.98901 1590RTA00000178AF.i.01.2 4 6 26 3.79182 2.98901 2624 RTA00000118A.j.24.1 1810 80 7.00028 6.65963 2743 RTA00000345F.j.09.1 13 12 148 10.7921 9.86174

TABLE 31 Differentially expressed polynucleotides: Higher expression innormal colon tissue (UC#2: lib15) vs. tumor potential colon tissue(UC#2: lib16) Lib15 Lib16 SEQ ID NO: Sequence Name Cluster ID clonesclones lib15/lib16 Zscore 1335 RTA00000196F.k.11.1 3 242 39 6.4476512.3988

Example 24 Polynucleotides Differentially Expressed in GrowthFactor-Stimulated Human Microvascular Endothelial Cells (HMEC) Relativeto Untreated HMEC

A number of polynucleotide sequences have been identified that aredifferentially expressed between human microvascular endothelial cells(HMEC) that have been treated with growth factors relative to untreatedHMEC.

Sequences that are differentially expressed between growthfactor-treated HMEC and untreated HMEC can represent sequences encodinggene products involved in angiogenesis, metastasis (cell migration), andother development and oncogenic processes. For example, sequences thatare more highly expressed in HMEC treated with growth factors (such asbFGF or VEGF) relative to untreated HMEC can serve as markers of cancercells of higher metastatic potential. Detection of expression of thesesequences in colon cancer tissue can be valuable in determiningdiagnostic, prognostic and/or treatment information associated with theprevention of achieving the malignant state in these tissues, and can beimportant in risk assessment for a patient. A patient sample displayingan increased level of one or more of these polynucleotides may thuswarrant closer attention or more frequent screening procedures to catchthe malignant state as early as possible.

The following table summarizes identified polynucleotides withdifferential expression between growth factor-treated and untreatedHMEC. TABLE 32 Differentially expressed polynucleotides: Higherexpression in bFGF treated HMEC (lib13) vs. untreated HMEC (lib12) Lib12Lib13 SEQ ID NO: Sequence Name Cluster ID clones clones lib13/lib12Zscore 1492 RTA00000199F.i.9.1 7 25 52 2.07199 2.94741

TABLE 33 Differentially expressed polynucleotides: Higher expression inVEGF treated HMEC (lib14) vs. untreated HMEC (lib12) Cluster Lib12 Lib14SEQ ID NO: Sequence Name ID clones clones lib14/lib12 Zscore 1492RTA00000199F.i.9.1 7 25 67 2.62449 4.17666 2743 RTA00000345F.j.09.1 1322 49 2.18114 2.99887

Example 25 Polynucleotides Differentially Expressed Across MultipleLibraries

A number of polynucleotide sequences have been identified that aredifferentially expressed between cancerous cells and normal cells acrossall three tissue types tested (i.e., breast, colon, and lung).Expression of these sequences in a tissue or any origin can be valuablein determining diagnostic, prognostic and/or treatment informationassociated with the prevention of achieving the malignant state in thesetissues, and can be important in risk assessment for a patient. Thesepolynucleotides can also serve as non-tissue specific markers of, forexample, risk of metastasis of a tumor. The following table summarizesidentified polynucleotides that were differentially expressed butwithout tissue type-specificity in the breast, colon, and lung librariestested. TABLE 34 Polynucleotides Differentially Expressed AcrossMultiple Library Comparisons Cell or Tissue Sample and Cancer SEQ IDClones in 1st Clones in 2nd State Compared NO. Cluster Lib Lib Ratio (ZScore) 2868 1605 lib1 lib2 lib1/lib2 colon: high met > low met 36 113.0342732 (3.2440104) lib8 lib9 lib8/lib9 lung: high met > low met 22 47.6861036 (4.2380835) 909 51 lib8 lib9 lib8/lib9 lung: high met > lowmet 348 66 7.3684960 (17.431560) lib18 lib19 lib19/lib18 pt #3 colon:tumor > normal 0 14 12.250507 (3.2325073) lib15 lib17 lib17/lib15 pt #2colon: met > normal 1 10 9.2702249 (2.2883061) 1018 3442 lib8 lib9lib9/lib8 lung: low met > high met 5 23 3.2916548 (2.3682625) lib3 lib4lib3/lib4 breast: high met > low met 17 4 4.1465504 (2.5623912) 10471827 lib8 lib9 lib8/lib9 lung: high met > low met 45 15 4.1924201(5.0989192) lib3 lib4 lib4/lib3 breast: low met > high met 37 1574.3491051 (8.7172773) 3089 213 lib8 lib9 lib9/lib8 lung: low met > highmet 137 403 2.1049458 (7.6610331) lib3 lib4 lib3/lib4 breast: high met >low met 17 4 4.1465504 (2.5623912) 1834 6268 lib8 lib9 lib8/lib9 lung:high met > low met 5 0 6.9873669 (2.1898837) lib3 lib4 lib4/lib3 breast:low met > high met 3 18 6.1496901 (3.1117967) 1096 8 lib8 lib9 lib8/lib9lung: high met > low met 1355 122 15.521118 (39.021411) lib19 lib20lib19/lib20 pt. #3 colon: tumor > met 14 1 10.471247 (2.5669948) lib18lib19 lib19/lib18 pt #3 colon: tumor > normal 1 14 12.250507 (2.8468716)1097 8 lib8 lib9 lib8/lib9 lung: high met > low met 1355 122 15.521118(39.021411) lib19 lib20 lib19/lib20 pt. #3 colon: tumor > met 14 110.471247 (2.5669948) lib18 lib19 lib19/lib18 pt #3 colon: tumor >normal 1 14 12.250507 (2.8468716) 3169 349 lib3 lib4 lib3/lib4 breast:high met > low met 77 1 75.125736 (8.3844087) lib1 lib2 lib2/lib1 colon:low met > high met 69 138 2.1571737 (5.2749799) 1939 4423 lib3 lib4lib3/lib4 breast: high met > low met 12 1 11.707907 (2.7293134) lib1lib2 lib2/lib1 colon: low met > high met 1 8 8.6286948 (2.1149516) 1968779 lib3 lib4 lib3/lib4 breast: high met > low met 60 22 2.6608879(3.9749537) lib1 lib2 lib2/lib1 colon: low met > high met 27 542.1571737 (3.2316908) 1231 1002 lib3 lib4 lib3/lib4 breast: high met >low met 42 20 2.0488837 (2.5703094) lib1 lib2 lib2/lib1 colon: low met >high met 12 65 5.8423454 (6.2625969) 1263 4769 lib8 lib9 lib8/lib9 lung:high met > low met 10 3 4.6582446 (2.2936274) lib3 lib4 lib4/lib3breast: low met > high met 2 20 10.249483 (3.6825426) 1264 4769 lib8lib9 lib8/lib9 lung: high met > low met 10 3 4.6582446 (2.2936274) lib3lib4 lib4/lib3 breast: low met > high met 2 20 10.249483 (3.6825426)2049 3500 lib3 lib4 lib3/lib4 breast: high met > low met 12 3 3.9026356(2.0180506) lib1 lib2 lib2/lib1 colon: low met > high met 3 13 4.6738763(2.4029818) 1335 3 lib1 lib2 lib1/lib2 colon: high met > low met 52682164 2.2570094 (32.965564) lib8 lib9 lib8/lib9 lung: high met > low met986 392 3.5150733 (22.468331) lib19 lib20 lib19/lib20 pt #3 colon:tumor > met 328 46 5.3331820 (11.896271) lib18 lib20 lib18/lib20 pt #3colon: normal > met 409 46 7.5999342 (15.399861) lib15 lib17 lib15/lib17pt#2 colon: normal > met 242 26 10.04 (13.789000) lib15 lib16lib15/lib16 pt#2 colon: normal > tumor 242 39 6.44765 12.39883 1396 35lib8 lib9 lib8/lib9 lung: high met > low met 868 11 110.27335(34.289704) lib3 lib4 lib4/lib3 breast: low met > high met 386 19675.2229880 (33.232871) 1404 1577 lib3 lib4 lib3/lib4 breast: high met >low met 25 3 8.1304909 (3.9038139) lib1 lib2 lib2/lib1 colon: low met >high met 12 40 3.5952895 (4.0199130) 1425 17 lib19 lib20 lib19/lib20 pt#3 colon: tumor > met 24 2 8.9753551 (3.4195074) lib18 lib19 lib19/lib18pt #3 colon: tumor > normal 4 24 5.2502174 (3.2458055) 1434 2444 lib3lib4 lib4/lib3 breast: low met > high met 26 55 2.1681599 (3.2224421)lib8 lib9 lib9/lib8 lung: low met > high met 12 37 2.2063628 (2.2999846)2198 211 lib3 lib4 lib3/lib4 breast: high met > low met 121 43 2.7454588(5.8560985) lib1 lib2 lib2/lib1 colon: low met > high met 109 2062.0384302 (6.0859794) 2231 1002 lib3 lib4 lib3/lib4 breast: high met >low met 42 20 2.0488837 (2.5703094) lib1 lib2 lib2/lib1 colon: low met >high met 12 65 5.8423454 (6.2625969) 1492 7 lib12 lib14 lib14/lib12HMEC: VEGF > untreated 25 67 2.6244913 (4.1766696) lib12 lib13lib13/lib12 HMEC: bFGF > untreated 25 52 2.0719962 (2.9474155) 1537 4lib8 lib9 lib8/lib9 lung: high met > low met 506 209 3.3833566(15.730912) lib3 lib4 lib4/lib3 breast: low met > high met 987 28072.9149240 (30.381945) lib19 lib20 lib19/lib20 pt#3 colon: tumor > met 268 2.4308253 (2.0970580) lib18 lib19 lib19/lib18 pt#3 colon: tumor >normal 6 26 3.7918237 (2.9890107) 1570 4 lib8 lib9 lib8/lib9 lung: highmet > low met 506 209 3.3833566 (15.730912) lib3 lib4 lib4/lib3 breast:low met > high met 987 2807 2.9149240 (30.381945) lib19 lib20lib19/lib20 pt#3 colon: tumor > met 26 8 2.4308253 (2.0970580) lib18lib19 lib19/lib18 pt#3 colon: tumor > normal 6 26 3.7918237 (2.9890107)1590 4 lib8 lib9 lib8/lib9 lung: high met > low met 506 209 3.3833566(15.730912) lib3 lib4 lib4/lib3 breast: low met > high met 987 28072.9149240 (30.381945) lib19 lib20 lib19/lib20 pt#3 colon: tumor > met 268 2.4308253 (2.0970580) lib18 lib19 lib19/lib18 pt#3 colon: tumor >normal 6 26 3.7918237 (2.9890107) 2624 18 lib19 lib20 lib19/lib20 pt#3colon: tumor > met 80 13 4.6027462 (5.5144093) lib18 lib19 lib19/lib18pt#3 colon: tumor > normal 10 80 7.0002899 (6.6596394) lib15 lib17lib17/lib15 pt#3 colon: met > normal 4 23 5.3303793 (3.2702852) 2743 13lib19 lib20 lib19/lib20 pt#3 colon: tumor > met 148 23 4.8128716(7.6861840) lib18 lib20 lib20/lib18 pt#3 colon: met > normal 12 232.2423439 (2.1607719) lib18 lib19 lib19/lib18 pt#3 colon: tumor > normal12 148 10.792113 (9.8617485) lib15 lib17 lib17/lib15 pt#2 colon: met >normal 14 80 5.2972714 (6.3458044) lib15 lib16 lib16/lib15 pt#2 colon:tumor > normal 14 50 3.4370927 (4.2243697) lib12 lib14 lib14/lib12 HMEC:VEGF > untreated 22 49 2.1811410 (2.9988774) 2759 1508 lib1 lib2lib1/lib2 colon: high met > low met 46 17 2.5087292 (3.2300592) lib3lib4 lib3/lib4 breast: high met > low met 21 5 4.0977674 (2.8791960)2823 48 lib8 lib9 lib8/lib9 lung: high met > low met 342 155 3.0834574(12.213852) lib3 lib4 lib4/lib3 breast: low met > high met 412 10202.5374934 (16.526285) 2851 1275 lib3 lib4 lib4/lib3 breast: low met >high met 15 32 2.1865564 (2.4185764) lib8 lib9 lib9/lib8 lung: low met >high met 10 42 3.0054239 3.1471113high met = high metastatic potential;low met = low metastatic potential;met = metastasized;tumor = non-metastasized tumor;Pt = patient;#2 = UC#2;#3 = UC#3;HMEC = human microvascular endothelial cell;bFGF = bFGF treated;VEGF = VEGF treated

Example 12 Polynucleotides Exhibiting Colon-Specific Expression

The cDNA libraries described herein were also analyzed to identify thosepolynucleotides that were specifically expressed in colon cells ortissue, i.e., the polynucleotides were identified in libraries preparedfrom colon cell lines or tissue, but not in libraries of breast or lungorigin. The polynucleotides that were expressed in a colon cell lineand/or in colon tissue, but were present in the breast or lung cDNAlibraries described herein, are shown in Table 35 (inserted beforeclaims). TABLE 35 Polynucleotides Specifically Expressed in Colon SEQ IDlib 1 lib 2 lib 15 lib 16 lib 17 lib 18 lib 19 lib 20 NO: Sequence Namecluster clones clones clones clones clones clones clones clones 847RTA00000197AF.e.24.1 39250 2 0 0 0 0 0 0 0 851 RTA00000197AR.e.12.122095 3 0 0 0 0 0 0 0 860 RTA00000196AF.e.16.1 39252 2 0 0 0 0 0 0 0 862RTA00000196AF.c.17.1 39602 2 0 0 0 0 0 0 0 865 RTA00000131A.g.19.2 365352 0 0 0 0 0 0 0 866 RTA00000187AR.o.10.2 8984 4 3 0 0 0 2 0 0 867RTA00000198R.b.08.1 22636 3 0 0 0 0 0 0 0 870 RTA00000200R.g.09.1 227853 0 0 0 0 0 0 0 873 RTA00000200AF.b.19.1 22847 3 0 0 0 0 0 0 0 875RTA00000200F.m.15.1 22601 3 0 0 0 1 0 0 0 881 RTA00000181AF.n.15.2 861281 0 0 0 0 0 0 0 882 RTA00000196R.k.07.1 22443 2 0 0 0 0 0 0 1 884RTA00000200AR.e.02.1 36059 2 0 0 0 1 1 1 0 892 RTA00000177AR.a.23.5 69954 2 0 0 0 0 0 0 893 RTA00000198R.o.05.1 26702 2 0 0 0 0 0 0 0 894RTA00000201R.a.02.1 35362 2 0 0 0 0 0 0 0 905 RTA00000197AF.h.11.1 222643 0 0 0 0 0 0 0 910 RTA00000199F.c.09.2 16824 3 1 0 0 0 0 0 0 919RTA00000180AR.h.19.2 84182 1 0 0 0 0 0 0 0 922 RTA00000199R.f.09.1 229073 0 0 0 0 0 0 0 923 RTA00000199AF.p.4.1 10282 3 3 0 0 0 0 0 0 929RTA00000200R.o.03.1 22807 3 0 0 0 0 0 0 0 930 RTA00000189AF.l.22.1 333331 1 0 0 0 0 0 0 931 RTA00000195AF.d.20.1 37574 2 0 0 0 0 0 0 0 936RTA00000198AF.j.18.1 22759 3 0 0 0 0 0 0 0 939 RTA00000180AF.g.3.1 90245 2 0 0 0 0 0 0 946 RTA00000199R.j.08.1 37844 2 0 0 0 0 0 0 0 947RTA00000199F.e.10.1 22906 3 0 0 0 0 0 1 0 949 RTA00000179AF.g.12.3 363902 0 0 0 0 0 0 0 952 RTA00000183AR.h.23.2 18957 3 0 0 0 0 0 0 0 953RTA00000197AF.d.12.1 39546 2 0 0 0 0 0 0 0 960 RTA00000181AR.k.24.3 70058 2 0 0 0 0 0 0 963 RTA00000181AR.k.24.2 7005 8 2 0 0 0 0 0 0 968RTA00000199AR.m.06.1 19122 3 0 0 0 0 0 0 0 973 RTA00000134A.d.10.1 189573 0 0 0 0 0 0 0 981 RTA00000181AF.m.4.3 13238 4 1 0 0 0 0 0 0 985RTA00000196AF.c.6.1 23148 3 0 0 0 0 0 0 0 986 RTA00000198AF.k.19.1 758791 0 0 0 0 0 0 0 987 RTA00000199R.h.09.1 76020 1 0 0 0 0 0 0 0 988RTA00000198AF.o.18.1 13018 4 0 0 0 1 0 0 0 992 RTA00000199F.h.17.2 362542 0 0 0 0 0 0 0 993 RTA00000181AR.h.06.3 87226 1 0 0 0 0 0 0 0 1010RTA00000198AF.f.21.1 22676 3 0 0 0 0 0 0 0 1017 RTA00000200AR.b.07.117125 4 0 0 0 0 0 0 0 1022 RTA00000200F.o.03.1 22807 3 0 0 0 0 0 0 01024 RTA00000199AF.j.12.1 22461 3 0 0 0 0 0 0 0 1029 RTA00000195AF.d.4.122766 3 0 0 0 0 0 0 0 1038 RTA00000200R.k.01.1 40049 2 0 0 0 0 0 0 01039 RTA00000198AF.c.10.1 77149 1 0 0 0 0 0 0 0 1042RTA00000197AR.e.07.1 86969 1 0 0 0 0 0 0 0 1043 RTA00000199R.c.09.116824 3 1 0 0 0 0 0 0 1050 RTA00000181AF.o.04.2 22205 3 0 0 0 0 0 0 01051 RTA00000199AF.l.19.1 22460 3 0 0 0 0 0 0 0 1052RTA00000198AF.h.22.1 22366 2 1 0 0 0 0 0 0 1055 RTA00000199AF.m.15.110101 3 0 0 0 0 0 0 0 1056 RTA00000197AF.j.9.1 13236 4 1 0 0 0 0 0 01074 RTA00000185AR.b.18.1 12171 3 2 0 0 0 0 0 0 1079RTA00000201AF.a.02.1 35362 2 0 0 0 0 0 0 0 1080 RTA00000183AR.h.23.118957 3 0 0 0 0 0 0 0 1082 RTA00000187AR.k.12.1 78415 1 0 0 0 0 0 0 01086 RTA00000198AF.m.17.1 77992 1 0 0 0 0 0 0 0 1087RTA00000181AF.m.15.3 12081 4 0 0 0 0 0 0 0 1092 RTA00000198R.c.14.139814 2 0 0 0 0 0 0 0 1093 RTA00000200R.o.03.2 22807 3 0 0 0 0 0 0 01095 RTA00000192AF.n.13.1 8210 2 6 0 0 0 0 0 0 1100 RTA00000184AR.e.15.116347 4 0 0 0 0 0 0 0 1104 RTA00000198R.m.17.1 77992 1 0 0 0 0 0 0 01114 RTA00000178R.l.08.1 39648 2 0 0 0 0 0 0 0 1122 RTA00000198AF.p.16.171877 1 0 0 0 0 0 0 0 1124 RTA00000193AF.b.18.1 7542 8 0 0 2 1 0 1 01128 RTA00000199F.d.10.2 22049 3 0 0 0 0 0 0 0 1131 RTA00000200AF.b.07.117125 4 0 0 0 0 0 0 0 1132 RTA00000181AR.i.06.3 19119 3 0 0 0 0 0 0 01133 RTA00000196F.k.07.1 22443 2 0 0 0 0 0 0 1 1138 RTA00000198AF.k.23.18995 2 5 0 0 0 0 0 0 1140 RTA00000196AF.f.20.1 22774 3 0 0 0 0 0 0 01144 RTA00000195AF.c.12.1 37582 2 0 0 0 0 0 0 0 1146 RTA00000186AF.d.l.240044 2 0 0 1 0 0 0 0 1151 RTA00000200F.n.05.2 18989 3 0 0 0 0 0 0 01152 RTA00000178AF.j.20.1 15066 4 0 0 0 0 0 0 0 1154RTA00000188AF.m.08.1 22155 3 0 0 0 0 0 0 0 1159 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RTA00000426F.m.18.1 62974 1 0 0 0 0 0 0 0 3041RTA00000522F.g.15.1 76536 1 0 0 0 0 0 0 0 3042 RTA00000522F.n.12.1 741171 0 0 0 0 0 0 0 3044 RTA00000424F.d.10.3 73110 1 0 0 0 0 0 0 0 3048RTA00000527F.c.04.1 23090 3 0 0 0 0 0 0 0 3050 RTA00000527F.h.21.1 376302 0 0 0 0 0 0 0 3051 RTA00000425F.c.07.1 76042 1 0 0 0 0 0 0 0 3053RTA00000525F.c.15.1 7692 2 0 0 0 0 0 0 0 3054 RTA00000424F.d.22.3 761891 0 0 0 0 0 0 0 3055 RTA00000523F.h.12.1 65745 1 0 0 0 0 0 0 0 3056RTA00000522F.g.22.1 77504 1 0 0 0 0 0 0 0 3059 RTA00000522F.j.12.2 743411 0 0 0 0 0 0 0 3060 RTA00000523F.i.08.1 65099 1 0 0 0 0 0 0 0 3062RTA00000425F.j.20.1 26760 1 0 0 0 0 0 0 0 3064 RTA00000427F.f.24.1 645721 0 0 0 0 0 0 0 3065 RTA00000527F.a.13.1 37740 2 0 0 0 0 0 0 0 3069RTA00000424F.a.09.4 77833 1 0 0 0 0 0 0 0 3071 RTA00000525F.f.07.1 375002 0 0 0 0 0 0 0 3072 RTA00000424F.j.07.1 79211 1 0 0 0 0 0 0 0 3073RTA00000424F.m.10.1 34251 1 1 0 0 0 0 0 0 3075 RTA00000522F.g.06.1 782211 0 0 0 0 0 0 0 3076 RTA00000424F.h.03.1 74447 1 0 0 0 0 0 0 0 3077RTA00000424F.n.06.1 74737 1 0 0 0 0 0 0 0 3078 RTA00000427F.c.22.1 639901 0 0 0 0 0 0 0 3079 RTA00000424F.k.12.1 77666 1 0 0 0 0 0 0 0 3080RTA00000425F.f.02.1 76982 1 0 0 0 0 0 0 0 3081 RTA00000427F.h.11.1 264941 0 0 0 0 0 0 0 3082 RTA00000425F.j.16.1 75631 1 0 0 0 0 0 0 0 3084RTA00000427F.f.17.1 63803 1 0 0 0 0 0 0 0 3085 RTA00000522F.o.18.1 763661 0 0 0 0 0 0 0 3086 RTA00000427F.j.22.1 66367 1 0 0 0 0 0 0 0 3087RTA00000426F.p.10.1 65845 1 0 0 0 0 0 0 0 3088 RTA00000522F.m.02.1 768341 0 0 0 0 0 0 0 3091 RTA00000425F.e.15.1 75921 1 0 0 0 0 0 0 0 3094RTA00000424F.n.13.1 74942 1 0 0 0 0 0 0 0 3095 RTA00000424F.g.14.1 748791 0 0 0 0 0 0 0 3096 RTA00000426F.e.17.1 64089 1 0 0 0 0 0 0 0 3100RTA00000427F.g.19.1 64611 1 0 0 0 0 0 0 0 3102 RTA00000522F.c.01.1 749381 0 0 0 0 0 0 0 3103 RTA00000522F.g.17.1 76486 1 0 0 0 0 0 0 0 3104RTA00000523F.j.17.1 63610 1 0 0 0 0 0 0 0 3105 RTA00000522F.n.14.1 734101 0 0 0 0 0 1 0 3107 RTA00000523F.e.20.1 65164 1 0 0 0 0 0 0 0 3108RTA00000424F.c.15.3 73533 1 0 0 0 0 0 0 0 3109 RTA00000426F.p.09.1 666651 0 0 0 0 0 0 0 3110 RTA00000522F.p.09.1 75204 1 0 0 0 0 0 0 0 3111RTA00000426F.m.21.1 64915 1 0 0 0 0 0 0 0 3112 RTA00000425F.j.21.1 773731 0 0 0 0 0 0 0 3114 RTA00000523F.h.21.1 41440 1 1 0 0 0 0 0 0 3115RTA00000427F.h.24.1 65193 1 0 0 0 0 0 0 0 3116 RTA00000425F.f.24.1 408411 1 0 0 0 0 0 0 3117 RTA00000425F.m.03.1 76045 1 0 0 0 0 0 0 0 3118RTA00000426F.m.08.1 63781 1 0 0 0 0 0 0 0 3119 RTA00000523F.d.24.1 647991 0 0 0 0 0 0 0 3120 RTA00000523F.c.14.1 66015 1 0 0 0 0 0 0 0 3121RTA00000523F.b.20.1 66492 1 0 0 0 0 0 0 0 3122 RTA00000522F.h.07.1 751491 0 0 0 0 0 0 0 3123 RTA00000527F.g.10.1 37820 2 0 0 0 0 0 0 0 3126RTA00000427F.i.22.1 63199 1 0 0 0 0 0 0 0 3128 RTA00000527F.n.07.1 159392 2 0 0 0 0 0 0 3129 RTA00000425F.e.09.1 75550 1 0 0 0 0 0 0 0 3130RTA00000427F.h.02.1 63652 1 0 0 0 0 0 0 0 3131 RTA00000426F.f.16.1 656131 0 0 0 0 0 0 0 3132 RTA00000425F.i.21.1 75305 1 0 0 0 0 0 0 0 3133RTA00000427F.k.19.1 62851 1 0 0 0 0 0 0 0 3135 RTA00000426F.g.16.1 414461 1 0 0 0 0 0 0 3136 RTA00000527F.l.05.1 13016 4 0 0 1 1 0 0 0 3137RTA00000426F.m.02.1 66237 1 0 0 0 0 0 0 0 3140 RTA00000522F.l.22.1 758011 0 0 0 0 0 0 0 3141 RTA00000427F.h.19.1 63047 1 0 0 0 0 0 0 0 3143RTA00000522F.g.21.1 77310 1 0 0 0 0 0 0 0 3145 RTA00000522F.g.20.1 776881 0 0 0 0 0 0 0 3148 RTA00000425F.k.20.1 74048 1 0 0 0 0 0 0 0 3150RTA00000522F.b.07.1 78634 1 0 0 0 0 0 0 0 3151 RTA00000426F.g.19.1 636721 0 0 0 0 0 0 0 3152 RTA00000525F.d.19.1 36860 2 0 0 0 0 0 0 0 3154RTA00000427F.d.10.1 40685 1 1 0 0 0 0 0 0 3157 RTA00000424F.a.05.4 779761 0 0 0 0 0 0 0 3159 RTA00000424F.a.05.1 77976 1 0 0 0 0 0 0 0 3160RTA00000522F.l.15.1 74691 1 0 0 0 0 0 0 0 3161 RTA00000425F.e.02.1 761431 0 0 0 0 0 0 0 3162 RTA00000525F.c.11.1 37895 2 0 0 0 0 0 0 0 3164RTA00000522F.c.14.1 75449 1 0 0 0 0 0 0 0 3165 RTA00000424F.m.08.1 194021 2 0 0 0 0 0 0 3166 RTA00000527F.f.18.1 37577 2 0 0 0 0 0 0 0 3168RTA00000522F.a.06.1 73662 1 0 0 0 0 0 0 0 3171 RTA00000522F.d.23.1 738681 0 0 0 0 0 0 0 3174 RTA00000523F.j.10.1 63384 1 0 0 0 0 0 0 0 3175RTA00000527F.p.08.1 36013 2 0 0 0 0 0 0 0 3177 RTA00000426F.f.17.1 663341 0 0 0 0 0 0 0 3178 RTA00000523F.j.21.1 36925 2 0 0 0 0 0 0 0 3183RTA00000523F.a.01.1 74923 1 0 0 0 0 0 0 0 3185 RTA00000427F.j.06.1 636761 0 0 0 0 0 0 0 3186 RTA00000424F.m.04.1 79017 1 0 0 0 0 0 0 0 3187RTA00000523F.i.17.1 65779 1 0 0 0 0 0 0 0 3190 RTA00000525F.c.18.1 242082 1 0 0 0 0 0 0 3191 RTA00000527F.e.09.1 37521 2 0 0 0 0 0 0 0 3192RTA00000424F.j.08.1 73972 1 0 0 0 0 0 0 0 3194 RTA00000527F.c.09.1 648591 0 0 0 0 0 0 0 3197 RTA00000523F.c.03.1 36913 2 0 0 0 0 0 0 0 3198RTA00000427F.k.21.1 62880 1 0 0 0 0 0 0 0 3200 RTA00000427F.d.09.1 664861 0 0 0 0 0 0 0 3201 RTA00000426F.n.17.1 66572 1 0 0 0 0 0 0 0 3204RTA00000426F.m.03.1 66480 1 0 0 0 0 0 0 0 3205 RTA00000424F.h.06.1 775521 0 0 0 0 0 0 0 3206 RTA00000425F.d.06.1 77660 1 0 0 0 0 0 0 0 3207RTA00000427F.e.12.1 62813 1 0 0 0 0 0 0 0 3210 RTA00000426F.n.23.1 181761 0 0 0 0 0 0 0 3211 RTA00000522F.m.19.1 41544 1 1 0 0 0 0 0 0 3212RTA00000522F.a.05.1 32611 1 1 0 0 0 0 0 0 3213 RTA00000427F.i.09.1 659161 0 0 0 0 0 0 0 3214 RTA00000424F.j.09.1 74387 1 0 0 0 0 0 0 0 3215RTA00000424F.n.11.1 73874 1 0 0 0 0 0 0 0 3217 RTA00000527F.e.13.1 375882 0 0 0 0 0 0 0 3219 RTA00000425F.j.19.1 77925 1 0 0 0 0 0 0 0 3220RTA00000522F.g.12.1 78783 1 0 0 0 0 0 0 0 3221 RTA00000523F.a.07.1 758041 0 0 0 0 0 0 0 3222 RTA00000425F.e.19.1 73409 1 0 0 0 0 0 0 0 3223RTA00000425F.n.19.1 78324 1 0 0 0 0 0 0 0 3228 RTA00000427F.k.07.1 637421 0 0 0 0 0 0 0 3231 RTA00000522F.a.17.1 79032 1 0 0 0 0 0 0 0 3232RTA00000527F.l.19.1 36856 2 0 0 0 0 0 0 0 3233 RTA00000424F.i.11.1 415691 1 0 0 0 0 0 0 3235 RTA00000424F.d.19.3 73180 1 0 0 0 0 0 0 0 3236RTA00000522F.j.09.2 78522 1 0 0 0 0 0 0 0 3237 RTA00000424F.m.24.1 770451 0 0 0 0 0 0 0 3238 RTA00000522F.j.19.2 76224 1 0 0 0 0 0 0 0 3242RTA00000527F.j.12.2 37503 2 0 0 0 0 0 0 0 3243 RTA00000522F.g.11.1 754321 0 0 0 0 0 0 0 3244 RTA00000522F.k.02.2 77622 1 0 0 0 0 0 0 0 3245RTA00000427F.e.13.1 66080 1 0 0 0 0 0 0 0 3246 RTA00000426F.f.18.1 632711 0 0 0 0 0 0 0 3247 RTA00000427F.a.12.1 63377 1 0 0 0 0 0 0 0 3248RTA00000424F.b.23.4 77322 1 0 0 0 0 0 0 0 3252 RTA00000427F.f.02.1 368222 0 0 0 0 0 0 0 3254 RTA00000424F.i.15.1 78043 1 0 0 0 0 0 0 0 3256RTA00000522F.m.03.1 79194 1 0 0 0 0 0 0 0 3257 RTA00000522F.a.20.1 740701 0 0 0 0 0 0 0 3258 RTA00000424F.b.15.4 74958 1 0 0 0 0 0 0 0 3259RTA00000527F.g.14.1 37532 2 0 0 0 0 0 0 0 3260 RTA00000522F.d.06.1 748091 0 0 0 0 0 0 0 3262 RTA00000427F.e.10.1 64599 1 0 0 0 0 0 0 0 3263RTA00000527F.c.16.1 22908 3 0 0 0 0 0 0 0 3265 RTA00000523F.f.17.1 639841 0 0 0 0 0 0 0 3267 RTA00000527F.p.24.1 36832 2 0 0 0 0 0 0 0 3268RTA00000425F.n.17.1 78304 1 0 0 0 0 0 0 0 3270 RTA00000425F.e.07.1 759921 0 0 0 0 0 0 0 3272 RTA00000523F.h.08.1 62893 1 0 0 0 0 0 0 0 3273RTA00000522F.o.10.1 78798 1 0 0 0 0 0 0 0 3274 RTA00000425F.l.10.1 268931 0 0 0 0 0 0 0 3275 RTA00000427F.f.16.1 64122 1 0 0 0 0 0 0 0 3278RTA00000425F.i.10.1 78736 1 0 0 0 0 0 0 0 3279 RTA00000426F.m.12.1 637401 0 0 0 0 0 0 0 3280 RTA00000527F.g.12.1 37746 2 0 0 0 0 0 0 0 3283RTA00000425F.i.18.1 42255 1 1 0 0 0 0 0 0 3285 RTA00000424F.j.13.1 744851 0 0 0 0 0 0 0 3289 RTA00000424F.k.10.1 73232 1 0 0 0 0 0 0 0 3290RTA00000522F.i.07.2 78377 1 0 0 0 0 0 0 0 3292 RTA00000522F.b.08.1 269151 0 0 0 0 0 0 0 3293 RTA00000522F.l.08.1 78781 1 0 0 0 0 0 0 0 3294RTA00000525F.a.14.1 37566 2 0 0 0 0 0 0 0 3295 RTA00000424F.g.08.1 749281 0 0 0 0 0 0 0 3296 RTA00000425F.l.09.1 75251 1 0 0 0 0 0 0 0 3297RTA00000522F.o.20.1 74853 1 0 0 0 0 0 0 0 3298 RTA00000527F.j.04.2 118093 1 0 0 0 0 0 0 3300 RTA00000523F.c.13.1 40668 1 1 0 0 0 0 0 0 3301RTA00000427F.i.21.1 65540 1 0 0 0 0 0 0 0 3303 RTA00000522F.h.02.1 749471 0 0 0 0 0 0 0 3304 RTA00000522F.g.10.1 74294 1 0 0 0 0 0 0 0 3308RTA00000425F.k.16.1 75282 1 0 0 0 0 0 0 0 3309 RTA00000525F.b.09.1 234722 1 0 0 0 0 0 0 3310 RTA00000522F.j.08.2 76613 1 0 0 0 0 0 0 0 3312RTA00000523F.f.19.1 34169 1 1 0 0 0 0 0 0 3313 RTA00000425F.j.18.1 755611 0 0 0 0 1 0 0 3314 RTA00000426F.m.04.1 36865 2 0 0 0 0 0 0 0 3315RTA00000527F.g.21.1 36028 2 0 0 0 0 0 0 0 3317 RTA00000525F.a.22.1 368482 0 0 0 0 0 0 0 3318 RTA00000522F.p.22.1 73322 1 0 0 0 0 0 0 0 3319RTA00000424F.d.12.2 74342 1 0 0 0 0 0 0 0 3320 RTA00000424F.g.24.1 791561 0 0 0 0 0 0 0 3321 RTA00000427F.a.10.1 65370 1 0 0 0 0 0 0 0 3322RTA00000426F.h.20.1 23187 3 0 0 0 0 0 0 0 3323 RTA00000424F.d.12.3 743421 0 0 0 0 0 0 0 3324 RTA00000425F.c.03.1 74643 1 0 0 0 0 0 0 0 3325RTA00000523F.f.16.1 26522 1 0 0 0 0 0 0 0 3326 RTA00000427F.f.15.1 667341 0 0 0 0 0 0 0 3329 RTA00000522F.p.18.1 76376 1 0 0 0 0 0 0 0 3337RTA00000522F.g.18.1 73226 1 0 0 0 0 0 0 0 3339 RTA00000522F.h.05.1 733581 0 0 0 0 0 0 0 3341 RTA00000425F.n.16.1 18265 1 0 0 0 0 0 0 0 3342RTA00000527F.l.21.1 36439 2 0 0 0 0 0 0 0 3345 RTA00000424F.d.17.3 739581 0 0 0 0 0 0 0 3346 RTA00000523F.j.02.1 62853 1 0 0 0 0 0 0 0

No clones corresponding to the colon-specific polynucleotides in thetable above resent in any of Libraries 3, 4, 8, 9, 12, 13, 14, or 15.The polynucleotide provided above can be used as markers of cells ofcolon origin, and find particular use in reference arrays, as describedabove.

Example 26 Identification of Contiguous Sequences Having aPolynucleotide of the Invention

The novel polynucleotides were used to screen publicly available andproprietary databases to determine if any of the polynucleotides of SEQID NOS: 845-3346 would facilitate identification of a contiguoussequence, e.g., the polynucleotides would provide sequence that wouldresult in 5′ extension of another DNA sequence, resulting in productionof a longer contiguous sequence composed of the provided polynucleotideand the other DNA sequence(s). Contiging was performed using theGelmerge application (default settings) of GCG from the Univ. ofWisconsin.

Using these parameters, 146 contiged sequences were generated. Thesecontiged sequences are provided as SEQ ID NOS:5951-6096 (see Table 17).The contiged sequences can be correlated with the sequences of SEQ IDNOS:845-3346 upon which the contiged sequences are based by, forexample, identifying those sequences of SEQ ID NOS: 845-3346 and thecontiged sequences of SEQ ID NOS: 5951-6096 that share the same clonename in Table 17.

The contiged sequences (SEQ ID NO: 5951-6096) thus represent longersequences that encompass a polynucleotide sequence of the invention. Thecontiged sequences were then translated in all three reading frames todetermine the best alignment with individual sequences using the BLASTprograms as described above for SEQ ID NOS: 845-3346 and the validationsequences “SEQ ID NOS:3347-5950.” Again the sequences were masked usingthe XBLAST program for masking low complexity as described above inExample 1 (Table 18). Several of the contiged sequences were found toencode polypeptides having characteristics of a polypeptide belonging toa known protein families (and thus represent new members of theseprotein families) and/or comprising a known functional domain (Table36). Thus the invention encompasses fragments, fusions, and variants ofsuch polynucleotides that retain biological activity associated with theprotein family and/or functional domain identified herein. TABLE 36Profile hits using contiged sequences SEQ Biological Activity ID NO(Profile) Start Stop Score Direction Sequence Name 5955 7tm_2 71 9158090 for RTA00000399F.o.01.1 5964 7tm_2 101 919 8475 revRTA00000341F.m.21.1 6018 7tm_2 3 963 9431 for RTA00000192AF.h.19.1 60417tm_2 214 1073 8528 rev RTA00000192AF.f.3.1 6052 ANK 546 629 4920 forRTA00000190AF.f.5.1 5964 asp 126 1067 6620 rev RTA00000341F.m.21.1. 6085asp 112 1094 6553 for RTA00000418F.i.06.1 6087 asp 347 1028 5981 forRTA00000339F.b.02.1 6041 ATPases 113 781 5690 for RTA00000192AF.f.3.16083 ATPases 1 348 15955 for RTA00000401F.m.07.1 6085 ATPases 110 8236782 for RTA00000418F.i.06.1 6087 ATPases 338 874 5832 forRTA00000339F.b.02.1 5969 protkinase 59 685 5791 for RTA00000182AF.c.5.16061 protkinase 75 1035 5405 for RTA00000181AF.p.12.3 6081 protkinase 25546 5107 rev RTA00000118A.n.5.1 6092 protkinase 14 422 5103 revRTA00000419F.k.05.1 6096 protkinase 89 755 5499 for RTA00000404F.m.17.25964 Wnt_dev_sign 3 948 11036 for RTA00000341F.m.21.1All stop/start sequences are provided in the forward direction.

Descriptions of the profiles for the indicated protein families andfunctional domains are provided in Example 3 above.

Those skilled in the art will recognize, or be able to ascertain, usingnot more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such specific embodimentsand equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Deposit Information:

The following materials were deposited with the American Type CultureCollection: CMCC=(Chiron Master Culture Collection) Cell Lines Depositedwith ATCC ATCC CMCC Cell Line Deposit Date Accession No. Accession No.KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-1253311611 MDA-MB-231 May 15, 1998 CRL-12532 10583 MCF-7 Oct. 9, 1998CRL-12584 10377 cDNA Libraries Deposited with ATCC cDNA Library No. cDNALibrary ES21 cDNA Library ES22 cDNA Library ES23 Deposit Date Jan. 22,1999 Jan. 22, 1999 Jan. 22, 1999 ATCC Accession No. ATCC No. ATCC No.ATCC No. Clone M00001575D:G05 M00001364A:E11 M00001489B:A06 NamesM00001460A:A03 M00001694C:H10 M00001585A:D06 M00001655C:E04M00003841D:E03 M00001637B:E07 M00001676C:C11 M00004176D:B12M00001529D:H02 M00001679D:D05 M00001387B:E02 M00001500C:C08M00001546B:C05 M00004282B:A04 M00001483B:D03 M00001453B:E10M00001376B:F03 M00001623C:H07 M00001445D:A06 M00003975B:F03M00001399C:H12 M00004208D:H08 cDNA Library No. cDNA Library ES24 cDNALibrary ES25 cDNA Library ES26 Deposit Date Jan. 22, 1999 Jan. 22, 1999Jan. 22, 1999 ATCC Accession No. ATCC No. ATCC No. ATCC No. CloneM00003987D:D06 M00001675D:B08 M00001479C:F10 Names M00004073A:H12M00001589B:E12 M00003842D:F08 M00004104B:F11 M00001607D:A11M00003901A:C09 M00004237D:D08 M00001636A:E07 M00003982A:B06M00004111D:B07 M00001530A:B12 M00003824A:A06 M00004138B:B11M00001495B:B08 M00003845D:C03 M00001391C:C04 M00001487C:F01M00003856A:B07 M00001448D:E12 M00001644B:D06 M00004104B:A02M00001450A:B03 M00003751C:A04 M00004110C:E03 M00001451B:F01

In addition, libraries of selected clones were deposited. The details ofthese deposits are provided in Tables 37-40.

This deposit is provided merely as convenience to those of skill in theart, and is not an admission that a deposit is required under 35 U.S.C.§112. The sequence of the polynucleotides contained within the depositedmaterial, as well as the amino acid sequence of the polypeptides encodedthereby, are incorporated herein by reference and are controlling in theevent of any conflict with the written description of sequences herein.A license may be required to make, use, or sell the deposited material,and no such license is granted hereby. TABLE 37 Clones Deposited on Jan.22, 1999 cDNA LIbrary Ref. Library ES17 Library ES18 Library ES19 ATCCNo 207064 207065 207066 Clone M00001601A:E09 M00001594A:D06M00003906A:F04 Names M00001368A:D07 M00001613D:H10 M00003908A:F12M00003917A:D02 M00001596D:E10 M00003914A:G09 M00001673A:A04M00001592C:G04 M00003915C:H04 M00003868B:G11 M00001599D:A09M00003905D:B08 M00003917C:D03 M00001619B:A09 M00003908C:G09M00003791C:E09 M00001593B:E11 M00003914B:A11 M00003870A:C05M00001605A:E06 M00003916C:C05 M00003922A:D02 M00001608A:D03M00003959A:A03 M00003861C:H02 M00001616C:A02 M00003905D:C08M00003931B:A11 M00001617A:D06 M00003908D:D12 M00001679D:B05M00001595C:E01 M00003901B:H04 M00001679C:D05 M00001616C:A11M00004031A:E01 M00001687A:G01 M00001608C:E11 M00004029C:C12M00003945A:E09 M00001610C:E06 M00003911A:F10 M00003908A:H09M00001612B:D11 M00003914C:F09 M00001649B:G12 M00001618B:E05M00003963D:B05 M00003813D:H12 M00001621C:C10 M00003986C:E09M00004087C:D03 M00001647A:H08 M00004031A:F07 M00004269B:C08M00001631D:B10 M00003907C:C02 M00004348A:A02 M00001608D:E09M00003911B:F08 M00001679C:D01 M00001641B:C10 M00003914C:H05M00001490A:E11 M00001641D:E02 M00003918C:C12 M00001387A:E10M00001630D:H10 M00003914C:C02 M00001397B:G03 M00001585C:D10M00003914A:E04 M00001441D:E04 M00001560A:H10 M00003903B:D03M00001352C:G09 M00001573B:C06 M00003905A:F09 M00001370D:A12M00001660C:D11 M00003867C:E11 M00001387B:A06 M00001641C:C05M00003870B:B08 M00001397C:A10 M00001578B:B05 M00003879D:A08M00001536D:G02 M00001587C:C10 M00003891D:B10 M00003895C:A10M00001590B:C07 M00003901C:A08 M00001464B:B03 M00001554A:E04M00003903C:C04 M00004370A:G05 M00001570C:G06 M00003905A:F10M00001490B:H11 M00001576A:B09 M00003906C:D06 M00001530B:D10M00001582A:H01 M00003907D:A12 M00001579C:E09 M00001582B:E12M00003905C:G11 M00001587A:H03 M00001615B:F07 M00003914D:D10M00001457C:H12 M00001571C:A04 M00003972A:G09 M00001535C:E01M00001573D:D10 M00003975D:C06 M00001561D:C05 M00001576A:F11M00003905C:B02 M00001589A:C01 M00001579C:G05 M00003907D:F11M00001664D:G07 M00001582D:A02 M00003914A:G06 M00001565A:H09M00001589B:E07 M00003914D:E03 M00001381C:B08 M00001575B:B02M00003972C:F08 M00001395C:F11 M00001578C:G06 M00003976C:D06M00001429D:F11 M00001591A:B08 M00003907C:C04 M00001449A:F01M00001607A:F11 M00003905B:C06 M00001391C:H02 M00001579C:E06M00004088C:A12 M00001429D:H12 M00001661C:F11 M00004103C:D04M00001450A:G11 M00001650B:C10 M00004107A:D01 M00001344B:F12M00001654C:E04 M00004110A:E04 M00001391D:C06 M00001656B:A08M00004062A:H06 M00003971A:A06 M00001662C:B02 M00004075D:C10M00001346A:E04 M00001656B:D05 M00004081D:H09 M00001455C:G07M00001661C:F10 M00004089A:B08 M00001402D:F02 M00001663A:C11M00004103D:F10 M00001438D:C06 M00001669A:C10 M00004107B:B04M00001349B:G05 M00001651B:B12 M00004032C:B02 M00001389C:A08M00001653B:E06 M00004078C:F04 M00001439B:A10 M00001659C:F02M00004038B:H10 M00001455B:A09 M00001661B:F03 M00004089A:E02M00001441B:D11 M00001663C:F10 M00004096B:F05 M00001453A:B01M00001669A:G12 M00004104C:H12 M00001456D:E08 M00001674D:C10M00004110D:A10 M00001399A:C03 M00001651B:E06 M00004036D:F02M00004496C:H03 M00001651C:C05 M00004088C:E04 M00004135D:G02M00001657C:C07 M00004104D:A04 M00004692A:E07 M00001662A:C12M00004107D:E12 M00004374D:E10 M00001663D:C06 M00004115D:D08M00004405D:C04 M00001590B:C05 M00003846A:D03 M00004312B:H07M00001483C:G06 M00004072C:F08 M00003976C:A10 M00001653A:G07M00004039B:G08 M00004043A:D02 M00001625B:C10 M00003986D:D02M00004081C:H06 M00001626C:D12 M00003914A:B07 M00004050D:A06M00001634D:D02 M00003914D:B02 M00001361B:C07 M00001641C:C06M00003971B:B07 M00004341B:G03 M00001642D:F02 M00003978C:A03M00001342B:E01 M00001647B:E04 M00003983B:C08 M00004064D:A11M00001632B:E05 M00004033D:D07 M00004087A:G08 M00001639A:C11M00004072D:H12 M00004344B:H04 M00001642D:G10 M00004077B:H11M00004497A:H03 M00001624A:G11 M00004080A:F01 M00001338C:E10M00001626C:G08 M00004092C:B03 M00001366D:E12 M00001672D:D04M00004037B:C04 M00001390D:E03 M00001639A:H06 M00004073C:D04M00001413B:H09 M00001662C:A04 M00004081A:A08 M00004271B:B06M00001641B:B01 M00004085B:B05 M00004151D:E03 M00001673C:A02M00004090C:C07 M00001660B:C04 M00001650A:A12 M00004086D:B09M00003802D:B11 M00001659D:D03 M00004088D:B03 M00001579C:E08M00001661B:B05 M00004090C:C10 M00001557D:C08 M00001671D:E10M00004102C:D09 M00003779B:E12 M00001652D:A06 M00004105C:E09M00001638A:D10 M00001654C:D05 M00004035A:G10 M00003794A:B03M00001656A:B07 M00003906A:H07 M00001616C:F07 M00001647B:C09M00004083B:G03 M00001679A:F01 M00001635A:C06 M00001675B:E02M00001604C:E09 M00001482D:A04 M00003793C:D09 M00001653B:E09M00001485C:B10 M00003762B:H09 M00001585A:F07 M00001457D:A07M00001694C:F12 M00003811D:A12 M00001461A:E05 M00001678D:C11M00001653C:F12 M00001477A:G07 M00001677D:B07 M00001679D:F06M00001479D:H03 M00001677B:A02 M00003751D:B02 M00001482C:D02M00001675B:H03 M00003801A:B10 M00001484D:G05 M00003808D:D04M00003844C:A08 M00001459B:D03 M00003752B:C02 M00001636C:C01M00001464B:C11 M00003819D:B11 M00001669C:B01 M00001511A:A05M00001677D:B02 M00003755A:A09 M00001477B:C02 M00001694C:G04M00003798D:H08 M00001471A:D04 M00003789C:F06 M00001444C:D05M00001485C:H10 M00001678C:C06 M00004040B:F10 M00001485D:E05M00001675B:D02 M00001355A:C12 M00001487C:G03 M00003750C:H05M00001401A:H07 M00001514A:B04 M00001694A:B12 M00001393B:B09M00001530C:G10 M00001677B:H06 M00001409D:F11 M00001534A:G06M00001675C:G01 M00001387B:H07 M00001539A:C12 M00001675B:C01M00001394C:C11 M00001547A:F11 M00003857B:F07 M00001344A:H07M00001550D:A04 M00003812B:D07 M00001490C:D07 M00001460A:F07M00001694B:B08 M00001352C:F06 M00001472C:A01 M00001677B:E06M00001476D:G03 M00001481B:A07 M00004037A:E04 M00001399C:D09M00001456D:F05 M00003870A:H01 M00001347C:G08 M00001456D:G11M00003842C:D11 M00001453D:G12 M00001477D:F10 M00003828B:F09M00001382A:F04 M00001481A:G06 M00003856C:H09 M00001392D:H04M00001464A:B03 M00003851A:C10 M00001429C:G12 M00001469A:G11M00003841C:E04 M00001454A:C11 M00001478B:D07 M00003837C:G08M00001517B:G08 M00001473A:C11 M00003828B:E07 M00001535A:D02M00001457A:G03 M00003772C:B12 M00001352A:E12 M00001669B:G02M00001677D:F03 M00001381B:F06 M00001479D:G06 M00001678B:B12M00004117A:D11 M00001473D:B11 M00001678D:G03 M00004217C:D03M00001475A:A12 M00001675C:F01 M00004270A:F11 M00001460A:G07M00003809A:H04 M00003996A:A06 M00001464A:D03 M00003771D:G05M00004056B:D09 M00001473D:G01 M00001678A:F05 M00004142A:B12M00001476D:C05 M00001677B:B06 M00001396D:B03 M00001484A:A10M00003794A:E12 M00001370D:E12 M00001457C:F02 M00003771B:E05M00001390C:C11 M00001459B:A12 M00001678A:A11 M00003989A:H11M00001464A:E07 M00003805B:C04 M00001426A:A09 M00001467A:B03M00001680B:E10 M00004498D:D05 M00001514A:B08 M00001679B:H07M00001391B:G12 M00001464A:B07 M00003904D:B12 M00001391D:D10M00001579A:C03 M00003856C:B08 M00001376B:A02 M00001517A:G08M00003858D:G06 M00001405B:D07 M00001530B:G09 M00003870B:F04M00001368A:A03 M00001538A:F12 M00003871C:B05 M00001392D:B11M00001540C:B03 M00003875A:C04 M00003900D:B10 M00001547A:F06M00003901B:A09 M00001494B:C01 M00001550A:F07 M00003901C:D03M00001352C:A05 M00001567B:G11 M00003904C:B06 M00001408B:G06M00001572A:A10 M00003901C:F09 M00004252C:E03 M00001575B:G01M00003904D:B10 M00003901C:A03 M00001487D:C11 M00003850D:H11M00004071D:A10 M00001577B:A03 M00003902B:D06 M00001377B:H01M00001539D:E10 M00003879A:C01 M00003939A:A02 M00001587A:F05M00003877D:G05 M00004250D:D10 M00001560A:F03 M00003881D:C12M00004290A:B03 M00001569B:G11 M00003903A:H09 M00003911D:B04M00001573A:A06 M00003905A:A06 M00004128B:G01 M00001575D:A10M00003875D:D09 M00004142A:D08 M00001583A:D01 M00003879B:A06M00003977A:E04 M00001587A:F08 M00003823D:G05 M00004236C:D10M00001590B:B02 M00003763A:C01 M00004388B:A08 M00001553A:E07M00003903B:C02 M00004409B:A11 M00001560A:H06 M00003905A:E07M00003965A:B11 M00001589C:A11 M00003867A:D12 M00003988A:E10M00001538A:C08 M00003857C:C09 M00004138A:H09 M00001531A:H03M00003829C:D10 M00003933C:D06 M00001548A:G01 M00003839D:E02M00004193C:G11 M00001531A:H07 M00003841C:F03 M00004039C:C01M00001542A:E04 M00003903D:C06 M00003924B:D04 M00001487A:F10M00003852D:E08 M00004375C:D01 M00001503C:G05 M00003845D:A09M00001511A:G08 M00003824A:G10 M00001539A:H12 M00003841C:F06M00001542A:F06 M00003848A:C09 M00001549A:F01 M00003857C:F11M00001514A:A12 M00003816C:C01 M00001516A:D05 M00003843A:E08M00001546C:C07 M00003850A:F06 M00001549A:H11 M00003813B:A11M00001538A:D03 M00003855C:F10 M00001544A:C09 M00003850D:B05M00001546B:F12 M00003841D:F06 M00001550A:D09 M00003858B:G05M00001487B:F02 M00003854D:A12 M00001513A:G07 M00003857C:G01M00001530A:F12 M00003816C:E09 M00001538A:D12 M00003813A:G04M00001587A:G06 M00003850D:A05 M00001551A:D04 M00001485B:C03

TABLE 38 Clones Deposited on Jan. 22, 1999 cDNA Ref No.; cDNA LibrarycDNA Ref Ref ES20 No. ES27 cDNA Library Ref ATCC No. 207067 ATCC No.207074 ATCC No. 207075 Clone M00004891D:A07 M00001623B:G07M00001550D:H02 Names M00004118B:C11 M00001619D:G05 M00001549C:D02 inM00004105A:B10 M00001616C:C09 M00001549A:A09 Library M00004099A:F11M00001615C:F03 M00001548A:B11 M00004037C:D07 M00001614D:D09M00001546C:G10 M00004033D:C05 M00001608B:A03 M00001544C:C06M00003983D:A09 M00001607D:F07 M00003820B:C05 M00004029B:H08M00001623D:C10 M00001543A:H12 M00004927A:A02 M00001599B:E09M00001540C:B10 M00003983C:F10 M00001632C:C09 M00001552B:G05M00003980B:C06 M00001605C:D12 M00001543C:F01 M00004033D:B07M00001625D:C07 M00001552D:G08 M00004034C:E08 M00001629B:E06M00001554B:B07 M00005100B:H07 M00001594A:B12 M00001555A:B01M00005136A:D10 M00001632C:A02 M00001557A:F01 M00005173D:H02M00001567C:H12 M00001558A:E11 M00004891D:C11 M00001635C:A03M00001561C:E11 M00004101A:F07 M00001636C:H09 M00001571D:B11M00003982B:B06 M00001638A:E07 M00001563B:D11 M00004108C:E01M00001639A:F10 M00001569C:B06 M00005136D:B07 M00001656C:G08M00001539B:H06 M00004118D:A11 M00001632A:F12 M00001571B:E03M00005102C:C01 M00001557A:D02 M00001561D:C11 M00005177C:A01M00001529B:C04 M00001487C:D06 M00004927C:H11 M00001534B:C12M00001454B:D08 M00005174D:B02 M00001535D:C01 M00003772D:E10M00004027A:D06 M00001536D:A12 M00001573C:D03 M00005217A:G10M00001540B:C09 M00001454D:E05 M00003984A:B06 M00001540D:D02M00001455D:F09 M00003851C:D07 M00001541C:B07 M00001457C:C11M00003959C:G06 M00001546B:B02 M00001459B:C09 M00005100B:G11M00001575B:C09 M00001460A:E01 M00005213C:G01 M00001554B:C07M00001460C:H02 M00003982B:H07 M00001578D:C04 M00001456A:H02M00004029C:B03 M00001557C:H07 M00001477B:F04 M00004033D:G06M00001558B:D08 M00003845D:B04 M00004091B:H09 M00001560D:A03M00001488A:E01 M00003959D:A04 M00001561C:F06 M00001492D:A11M00004030D:B06 M00001564D:C09 M00001496C:G10 M00004034C:C06M00003748B:F02 M00001499A:A05 M00004030C:D12 M00001570D:A03M00001500A:B02 M00003982C:H10 M00001660C:B12 M00001500D:E10M00003971C:F09 M00001577B:H02 M00001513D:A03 M00004031B:A06M00001548A:A08 M00001528A:C11 M00003966B:D02 M00003868B:D12M00001528C:H04 M00004028B:G08 M00001718D:F07 M00001531B:E09M00004031C:H10 M00003829C:A11 M00001463A:F06 M00004076D:B09M00003832B:E01 M00003755A:B03 M00004092D:B11 M00003842B:D09M00001653B:G07 M00003981C:F05 M00003845A:H12 M00001654D:G11M00004031D:F05 M00003847B:G03 M00001656B:A07 M00004097B:D03M00003847C:E09 M00001664B:D06 M00003986D:G07 M00003853D:G08M00001664C:H10 M00004033B:C02 M00003828A:E04 M00001680B:C01M00004037B:A04 M00003867C:H09 M00001681A:F03 M00004092C:B12M00003822A:F02 M00001684B:G03 M00005140D:G09 M00003868C:H10M00001771A:A07 M00004897D:G05 M00003871A:A05 M00003774C:D02M00004960B:D12 M00003879C:G10 M00003754D:D02 M00005134C:G04M00003880C:F10 M00001640B:F03 M00005139A:F01 M00003881D:D06M00003763B:H01 M00005176A:C12 M00003884D:G07 M00003812C:A05M00005178A:A07 M00003887A:A06 M00003803C:D09 M00005212A:A02M00003889A:D10 M00003801B:B10 M00005229D:H07 M00003889D:B09M00003798D:E03 M00004115C:H04 M00003858D:F12 M00003773B:G01M00004687A:C03 M00003774B:B08 M00003771A:G10 M00004900C:E11M00001680D:D02 M00001452A:E07 M00004695B:E04 M00001528A:F09M00004029B:F11 M00005134D:A06 M00003748A:B07 M00003751B:A05M00004103B:B07 M00001655A:F06 M00001609B:A11 M00005177A:B06M00003750A:D01 M00001573D:F10 M00005178A:A08 M00003761D:E02M00001579C:B11 M00004104D:B05 M00003763D:E10 M00001579C:H10M00004117B:G01 M00003768A:E02 M00001579D:G07 M00004900D:B10M00003829B:G03 M00001583B:E10 M00005134D:H03 M00003772A:D07M00001586D:E02 M00005173C:A02 M00001661B:C08 M00001587D:A10M00005177A:H09 M00003778A:D08 M00001589A:D12 M00005178B:H01M00003799A:D09 M00001590C:H08 M00005216C:B09 M00003800A:C09M00001651B:A11 M00003826B:E11 M00003804A:H04 M00001597A:E12M00001596A:G06 M00003806D:G05 M00001649C:B10 M00005100B:D02M00003808C:B05 M00001614A:E06 M00005137A:E01 M00003811A:E03M00001615C:D02 M00004119A:A06 M00003815D:H09 M00001621D:D03M00004891D:E07 M00003818B:G12 M00001623D:G03 M00004958B:D01M00003769B:D03 M00001624A:F09 M00005102C:F09 M00001390A:A09M00001624C:A06 M00005136D:C01 M00001432A:E06 M00001630B:A11M00005174D:H02 M00001381A:D02 M00001634B:C10 M00005177C:B04M00001383A:G04 M00001639D:B07 M00005218B:D09 M00001384C:E03M00001573D:F04 M00004102C:F03 M00001384C:F12 M00001595B:A09M00004114B:D09 M00001384D:H07 M00004156B:A12 M00004119D:A07M00001385B:F10 M00004319D:G09 M00004895C:G05 M00001385C:H11M00004096A:G02 M00004235A:A12 M00001386A:C02 M00004101C:G08M00005134B:E01 M00001372C:F07 M00004102A:H02 M00004115C:G03M00001389D:G11 M00004108A:A09 M00005175B:H04 M00001371D:G01M00004111D:D11 M00005214B:D11 M00001392C:D10 M00004115D:C08M00004102D:B05 M00001392D:H06 M00004118D:E08 M00004115A:B12M00001397B:B09 M00004121C:F06 M00004119D:H06 M00001398A:G03M00004131B:H09 M00004897D:F03 M00001400A:F06 M00004141D:A09M00004960B:A09 M00001410B:G05 M00004090A:F09 M00005134C:E11M00001413A:F02 M00004146A:C08 M00005138B:D12 M00001415B:E09M00004078B:A11 M00005176A:A05 M00001425A:C11 M00004176B:E08M00005214C:A09 M00001386A:D11 M00004188C:A09 M00004102C:D01M00001354C:B06 M00004233C:H09 M00004960B:A08 M00001339D:G02M00004241D:F11 M00001476D:A09 M00001660A:C12 M00004246C:A09M00001572A:B06 M00001528A:A01 M00004247C:C12 M00005217D:F12M00001343D:C04 M00004248B:E08 M00005233A:G08 M00001347B:E01M00004257C:H06 M00005236B:F10 M00001348A:D04 M00004260D:C12M00005259B:C01 M00001349C:C05 M00004295B:D02 M00005254D:B08M00001350A:D06 M00004040D:F01 M00005259C:B05 M00001352D:C05M00004142D:E10 M00001575A:D06 M00001380C:E05 M00003853D:D03M00005259D:H08 M00001354B:B10 M00003860D:H07 M00003813C:D08M00001380C:F02 M00003878C:E04 M00001530D:E06 M00001354C:C10M00003879A:G05 M00004891B:B12 M00001355B:G11 M00003880B:C08M00001596B:C11 M00001356D:F06 M00003881A:D09 M00004300C:H09M00001360D:E11 M00003881C:G09 M00001486D:D12 M00001361C:H11M00003901B:A05 M00001585D:F03 M00001362C:A10 M00003904D:D10M00001596B:D09 M00001363C:H02 M00003905C:G10 M00001570D:E06M00001366D:G02 M00003906B:F12 M00001582C:E01 M00001369A:H12M00003909A:H04 M00001586C:E06 M00001352D:D02 M00004091B:D11M00001593B:D10 M00001485D:B10 M00003963A:E03 M00001595C:H11M00001457B:E03 M00004353C:H07 M00001596B:H05 M00001457C:C12M00003919A:A10 M00001576A:C11 M00001458C:E01 M00003938A:B04M00001596C:F09 M00001462B:A10 M00003939C:F04 M00001567A:H05M00001464D:F06 M00003946D:C11 M00001585D:D11 M00001467D:H05M00003979A:F03 M00004688A:A02 M00001468B:H06 M00003985C:F01M00004927A:E06 M00001505C:H01 M00003997B:G07 M00005229D:H09M00001470A:H01 M00003860D:A01 M00004117B:A12 M00001457A:B07M00004035A:A04 M00004187D:G09 M00001479B:A01 M00004042D:H02M00005173B:F01 M00001469D:D02 M00004073B:B01 M00005218A:G05M00001487A:A05 M00003946A:H10 M00004118A:H08 M00001352C:H02M00001423D:A09 M00005134A:D11 M00001488D:C10 M00004314B:G07M00005176C:C09 M00001490C:C12 M00001405D:D11 M00005230D:F06M00001493B:D09 M00001408A:H04 M00005234D:B04 M00001504D:D11M00001408D:D04 M00005101C:E09 M00001376B:C06 M00001411D:F05M00004206A:E02 M00001506B:D09 M00001412A:E04 M00001570C:A05M00001511B:C06 M00001413A:F03 M00005231A:H04 M00001476B:F10M00001417B:C04 M00005235A:A03 M00001450D:D04 M00001417D:A04M00004118B:B04 M00001433A:G07 M00001418B:F07 M00005136D:D06M00001470C:B10 M00001419D:C10 M00005231C:B01 M00001437D:C04M00001402B:F12 M00004153B:B03 M00001447C:C01 M00001423A:G05M00004897C:D06 M00001448B:F06 M00001401C:H03 M00005136D:G06M00001449D:A06 M00001423D:D12 M00005212B:A02 M00001433B:H11M00001424B:H04 M00005232A:C10 M00001451D:C10 M00001428B:A09M00004692A:H10 M00001452A:C07 M00001430A:A02 M00005101C:B09M00001453C:A11 M00001432D:F05 M00004144A:F04 M00001456B:C09M00001438B:B09 M00003852B:D11 M00001454B:G03 M00001445B:E04M00001660D:E05 M00001454B:G07 M00001445C:A08 M00003808A:F09M00001454C:C08 M00001446C:D09 M00001656A:D10 M00001454C:F02M00001448A:G09 M00001671A:H06 M00001454D:D06 M00001449C:H12M00003809C:H07 M00001456B:F10 M00001422C:F12 M00003853C:C06M00001455D:A09 M00001352C:H10 M00003860A:A08 M00001455D:A11M00004375A:H01 M00003822B:D08 M00001448D:F09 M00004380B:A05M00003845A:E12 M00004444B:D11 M00003854C:C02 M00001338B:E02M00003860B:G09 M00003822B:G01 M00001344A:G07 M00001670A:C11M00001345A:G11 M00003852A:B03 M00001345B:E10 M00003829D:A11M00001345C:B01 M00003854C:F01 M00001346B:B07 M00003856B:C04M00001405B:E09 M00003905A:H11 M00001352B:F04 M00001530A:F11M00001451C:E01 M00003840B:E07 M00001361A:H07 M00003905B:G03M00001362B:H06 M00003840B:E08 M00001372C:G12 M00003855A:C12M00001375B:G12 M00003905B:H05 M00001376A:C05 M00003826B:B04M00001376B:A08 M00003851C:B06 M00001377C:E12 M00003853B:C08M00001382B:F12 M00003829A:F03 M00001385A:F12 M00001638C:G01M00001394A:E04 M00003845D:B02 M00001395A:C09 M00001653B:G07M00001396A:H03 M00001578B:A02 M00001350B:G11 M00001590B:H10M00001595C:A09 M00001596A:E07 M00001607A:B06 M00001607A:D10M00001652C:B09 M00001671B:F02 M00001632C:D08 M00001638C:H07M00001652D:B09 M00001614C:E11 M00001633B:B11 M00001651C:A04M00001639D:G12 M00001671C:F11 M00001638A:B04 M00001637C:H12M00001669B:H06 M00001639D:F02 M00001590A:C08 M00001636A:C02M00001614A:A04 M00001639D:G06

TABLE 39 Library Deposited on Jan. 22, 1999 cDNA Ref No.; cDNA LibraryRef ES29 cDNA Library Ref ES30 ATCC Accession No. ATCC No. 207076 ATCCNo. 207077 Clone Names in M00001449D:B01 M00001594D:B08 LibraryM00001476D:F03 M00001593A:B07 M00001456C:B12 M00001594A:C01M00001469B:B01 M00001594A:D08 M00001471A:B04 M00001594A:G09M00001472A:D08 M00001595C:B05 M00001473A:A07 M00001594B:F12M00001473C:D09 M00001596D:E03 M00001475B:C04 M00001594D:C03M00001475C:G11 M00001592C:F11 M00001476A:D11 M00001590D:G07M00001476B:D10 M00001595D:A04 M00001468A:C05 M00001595D:G03M00001476C:C11 M00001601A:A06 M00001467A:H07 M00001590C:F10M00001477B:E02 M00001589B:B08 M00001478B:H08 M00001589C:E06M00001479C:E01 M00001611B:A05 M00001480A:D03 M00001601A:E02M00001480C:A05 M00001587A:D01 M00001481A:H08 M00001591B:B12M00001481B:D09 M00001590B:G08 M00001482A:H05 M00001592C:E05M00001482D:H11 M00001591B:B06 M00001483C:G09 M00001591D:C07M00001485A:C05 M00001591D:F06 M00001476B:F08 M00001592A:E02M00001460A:E11 M00001592A:H05 M00001456C:C11 M00001592B:A04M00001457A:C05 M00001587A:B10 M00001457A:G12 M00001609D:G10M00001458A:A11 M00005231D:B09 M00001458C:D10 M00001614B:E08M00001458D:A01 M00005217C:C01 M00001458D:A02 M00001587A:B01M00001458D:C11 M00001613D:B03 M00001458D:D01 M00001613A:F03M00001459B:C11 M00001611C:H11 M00001468A:H10 M00001611C:C12M00001460A:C10 M00001611B:E06 M00001485B:F05 M00001611B:A09M00001460A:H11 M00001610D:D05 M00001461A:F05 M00001610B:C07M00001462A:D03 M00001610C:E07 M00001464A:B02 M00001610A:E09M00001464A:E10 M00001601A:E12 M00001465A:B12 M00001609B:C09M00001465A:C12 M00001608D:D11 M00001465A:E10 M00001608B:A09M00001465A:G06 M00001607D:F06 M00001466A:F08 M00001607B:C05M00001467A:C10 M00001606A:H09 M00001460A:B12 M00001605A:H03M00001545A:B12 M00001605A:E09 M00001535A:D10 M00001605A:A06M00001536A:F11 M00001604A:C11 M00001537A:H05 M00001604A:C07M00001539A:E01 M00001604A:B08 M00001539A:H02 M00001604A:A09M00001539B:G07 M00001610A:H05 M00001539D:B10 M00005214B:A06M00001540D:E02 M00005228A:A09 M00001541B:E05 M00001567A:B09M00001542A:G12 M00001561A:D01 M00001485B:D09 M00001559A:C08M00001545A:B10 M00001559A:A11 M00001533A:G05 M00001558A:G09M00001545A:F02 M00001555A:B12 M00001545A:G05 M00001554A:A08M00001546A:D08 M00001552A:H10 M00001548A:H04 M00001552A:F06M00001550A:E07 M00005231C:B07 M00001551A:A11 M00005218D:G10M00001551A:D06 M00001570A:H01 M00001551A:H06 M00005214D:D10M00001551D:H07 M00001570C:G03 M00001552A:E10 M00005213C:A01M00001450A:B08 M00005212D:F08 M00001544A:F05 M00005212A:D10M00001512A:G05 M00005211C:E09 M00001483B:D04 M00005211A:E09M00001485B:H03 M00005210D:C09 M00001485C:C08 M00005179D:B03M00001486B:D07 M00005179B:H02 M00001486B:E12 M00005177D:F09M00001487B:A11 M00005177C:G04 M00001487B:E10 M00005177B:H02M00001507A:A11 M00001614D:B08 M00001507A:B02 M00001615A:D06M00001507A:C05 M00005216B:D02 M00001507A:E04 M00001579C:A01M00001534A:D03 M00001585B:C03 M00001511A:G01 M00001585B:A06M00001533D:A08 M00001584D:H02 M00001513A:F05 M00001584A:G03M00001514A:G03 M00001583D:B08 M00001516A:D02 M00001583B:F02M00001516A:F06 M00001583A:F07 M00001517A:B11 M00001583A:A05M00001529D:C05 M00001582D:F02 M00001530A:A09 M00001582D:B01M00001530A:E10 M00001582A:A03 M00001532A:C01 M00001579D:H09M00001532D:A06 M00001567D:B03 M00001485B:D10 M00001579C:H06M00001511A:A02 M00001585B:F01 M00004249D:B08 M00001579B:F04M00004185D:E04 M00001579A:E03 M00004188D:G08 M00001578C:F05M00004197C:F03 M00001577D:H06 M00004198B:D02 M00001577B:F10M00004204D:C03 M00001576C:G05 M00004208B:F05 M00001575D:D12M00004208D:B10 M00001575D:B10 M00004210B:B05 M00001575D:A02M00001362D:H01 M00001573B:G08 M00004216D:D03 M00001573A:E01M00004167A:H03 M00001572A:B05 M00004275A:B03 M00001571D:F05M00004285C:A08 M00001579D:F04 M00004316A:G09 M00001636A:F08M00004465B:D04 M00001643B:E05 M00004493B:D09 M00001642C:G02M00001347B:H04 M00001642A:F03 M00001351C:B06 M00001641D:C04M00001360A:G10 M00001641C:H07 M00004216D:C03 M00001641C:F01M00004076D:D04 M00001641C:D02 M00001484C:A04 M00001641B:F12M00001456B:G01 M00001634A:B04 M00003972D:C09 M00001636B:G11M00003974C:E04 M00001649C:D05 M00003979A:E11 M00001636A:C03M00003983C:F03 M00001635D:D05 M00003989B:F11 M00001635D:C12M00004031D:B05 M00001635B:H02 M00004177C:A01 M00001635B:H01M00004076B:G03 M00001634D:G11 M00004167D:A07 M00001634D:D04M00004078A:A06 M00001634A:H05 M00004085A:B02 M00001641A:A11M00004107B:A06 M00001638B:E12 M00004111C:E11 M00001640A:H02M00004130D:H01 M00001614C:E06 M00004157D:B03 M00001636D:F09M00004159C:F09 M00001637A:A03 M00004162C:A07 M00001637A:A06M00004135B:G01 M00001637A:E10 M00004040A:G12 M00001637A:F10M00001453B:H12 M00001637C:C06 M00001448A:E11 M00001644A:H01M00001448B:F09 M00001638B:E03 M00001448B:H05 M00001649A:E11M00001448C:E11 M00001638B:F10 M00001448C:F10 M00001639A:C03M00001448D:F12 M00001639A:G07 M00001449B:B03 M00001639B:H01M00001449C:C05 M00001639B:H05 M00001449D:G10 M00001639C:A09M00001448A:B12 M00001639C:C02 M00001453A:D08 M00001649C:E11M00001451B:A04 M00001649C:H10 M00001454A:F11 M00001637C:E03M00001454A:G03 M00001617A:A08 M00001455A:F04 M00001622A:H12M00001455B:E07 M00001621C:H12 M00001455D:A06 M00001621B:G05M00001364B:B06 M00001620D:H02 M00004117A:G01 M00001620D:G11M00001455D:D11 M00001619D:D10 M00001456B:A06 M00001619C:C07M00001451A:C10 M00001619A:E05 M00001395A:E03 M00001623A:F04M00001366D:C06 M00001618A:A03 M00001365A:H10 M00001618B:D09M00001366D:C12 M00001617A:A01 M00001373D:B03 M00001616D:C11M00001453B:F08 M00001615C:G05 M00001444D:C01 M00001615C:A11M00001375B:C06 M00001615B:G07 M00001392C:D05 M00001633D:H06M00001395A:A12 M00001639C:A10 M00001395A:H02 M00001615B:A09M00001397D:G08 M00001615B:G01 M00001434A:B10 M00001618A:F10M00001416A:D09 M00001632C:H07 M00001433C:F10 M00001633D:D12M00001416A:H02 M00001633D:D09 M00001428D:B10 M00001618A:F08M00001428B:D01 M00001633D:G09 M00001426D:D12 M00001624A:A03M00001400C:D02 M00001633C:F09 M00001427C:D01 M00001633C:H05M00001633C:B09 M00001633A:E06 M00001633C:H11 M00001632C:B10M00001625D:G10 M00001631D:G05 M00001629C:E07 M00001629B:B08M00001626C:E04 M00001626C:C11 M00001632A:B10 M00001624B:B10M00001633C:A05 M00001625C:G05

TABLE 40 Clones Deposited on Jan. 22, 1999 cDNA Ref No.; cDNA LibraryRef ES31 cDNA Ref No. ES32 cDNA Library Ref ES33 ATCC Accession No. ATCCNo. 207078 ATCC No. 207079 ATCC No. 207080 Clone Names in M00003843A:E04M00003906A:F12 M00005254D:A10 Library M00003842C:G03 M00003906B:H06M00005260B:E11 M00003842A:A03 M00003906C:C05 M00005260A:F04M00003841D:A04 M00003907A:F01 M00005260A:A12 M00003841B:E06M00003907B:C03 M00005259B:D12 M00003841C:H11 M00003907B:D05M00005257D:H11 M00003844A:A11 M00003918A:D08 M00005257D:G07M00003841C:F01 M00003918A:F09 M00005257D:A06 M00003841C:H08M00003918C:H10 M00005257C:G01 M00003841C:D07 M00003924A:D08M00005257A:H11 M00003844D:A07 M00003958B:E11 M00005236B:H10M00003845D:G08 M00003958B:H08 M00005236B:G03 M00003852C:B06M00003960A:G07 M00005257C:E05 M00003854B:A07 M00003971B:A10M00001608C:D02 M00003854B:D04 M00003972D:H02 M00001608C:G04M00003859D:C05 M00003973C:C03 M00001608D:F11 M00003860B:F11M00003974B:B11 M00001609C:A12 M00003867B:G07 M00003974D:F02M00001609C:G05 M00003867B:G08 M00003974D:H04 M00001610C:B07M00003841B:E03 M00003975C:F07 M00001612D:D12 M00003822D:B10M00003977C:A06 M00001612D:F06 M00003867D:A06 M00003977C:B03M00001613A:D02 M00003868B:G06 M00003977D:A03 M00001614A:B10M00003867B:D10 M00003977D:A06 M00001614C:G07 M00003831C:G05M00003977D:D04 M00001615C:E07 M00003901C:B01 M00003978D:G04M00001625C:F10 M00003868C:C07 M00003980A:F04 M00001626D:A02M00003820A:A08 M00003980B:C11 M00001629A:H09 M00003820B:D07M00003981C:B04 M00001629D:B10 M00003820B:D10 M00003982A:B12M00001629D:D10 M00003822D:C06 M00003982C:G04 M00001630C:F09M00003823B:F07 M00003984D:B08 M00001631A:D03 M00003824C:D07M00003985B:G04 M00001631A:F06 M00003825B:B10 M00003985D:E10M00001631A:F12 M00003825B:B11 M00003986B:A08 M00001631B:H04M00003828A:D05 M00003986C:D09 M00001633A:F11 M00003822D:D04M00003986D:C08 M00001633A:G10 M00003830C:A03 M00003987B:E12M00001633B:A12 M00003840D:H10 M00003987B:F08 M00001633B:E03M00003832A:A09 M00003987C:G03 M00001633C:A08 M00003833B:B03M00003988D:A08 M00001633C:E12 M00003833B:C12 M00003989C:D03M00001635B:B02 M00003834B:G04 M00003989C:G05 M00001636A:H12M00003835A:A09 M00003989D:F12 M00001638A:C08 M00003835B:H11M00004029B:F01 M00001638B:C08 M00003835D:G06 M00004029C:C05M00001639D:C12 M00003837C:E05 M00004029C:G10 M00001640A:F05M00003837C:F10 M00004030D:F11 M00001642D:G08 M00003839A:D07M00004034A:A01 M00001647D:G07 M00003839D:E11 M00004034C:G02M00001649A:E10 M00003829C:H05 M00004034D:E09 M00001650D:D10M00003901B:C03 M00004035B:H09 M00001650D:F11 M00003878C:F06M00004036D:B04 M00001651C:D11 M00003878C:G08 M00004036D:B09M00001651C:G12 M00003879A:A02 M00004038A:F02 M00001652B:D06M00003879A:B08 M00004038D:G06 M00001652D:G02 M00003879A:C11M00004039A:C03 M00001652D:G06 M00003879A:D02 M00004039A:H11M00001653A:A05 M00003879B:G02 M00004039B:A05 M00001653D:H07M00003880B:D11 M00004039B:E12 M00001654A:E08 M00003880C:E11M00004040C:A01 M00001654B:A01 M00003880C:H03 M00004051D:E01M00001654C:D10 M00003901B:F10 M00004072D:F09 M00001654C:G07M00003890B:C08 M00004073A:D10 M00001654C:G09 M00003877C:A11M00004075B:G09 M00001655C:C07 M00003819D:B01 M00004076A:D12M00001655D:E08 M00003901B:G11 M00004076D:H07 M00001655D:H11M00001692A:G06 M00004078A:C11 M00001656A:H12 M00003903C:C05M00004078A:E05 M00001656C:C04 M00003903C:E12 M00004078A:F07M00001656D:C04 M00003903D:C12 M00004078B:C11 M00001657C:C11M00003903D:D10 M00004078B:F12 M00001657D:A10 M00003903D:H11M00004079D:G08 M00001659D:A09 M00003904A:C04 M00004081A:E02M00001661D:D05 M00003904B:C03 M00004081A:G01 M00001664B:E08M00003904C:A08 M00004081C:A10 M00001664B:F06 M00003881B:F10M00004083A:E08 M00001669B:C12 M00003871D:G06 M00004083B:C01M00001669C:B09 M00003868D:D09 M00004086D:G08 M00001670A:F09M00003868D:D11 M00004087B:A12 M00001678C:F09 M00003870C:A01M00004087C:A01 M00001693A:H06 M00003870C:A10 M00004088C:F01M00003805D:E06 M00003870C:E10 M00004088D:A11 M00003806C:A06M00003871A:A02 M00004088D:B05 M00003809B:A03 M00003871A:B09M00004088D:B10 M00003810A:A02 M00003871A:C11 M00004090B:B04M00003810B:B11 M00003871A:G09 M00004090B:H06 M00003810C:B06M00003871C:E04 M00004092B:E05 M00003810D:H09 M00003871C:F12M00004093C:C02 M00003811C:C02 M00003878C:D08 M00004096D:H03M00003813B:F02 M00003871D:E11 M00004099D:F01 M00003813C:H08M00003877C:G12 M00004100B:C07 M00003813D:B12 M00003875A:A07M00004103B:E09 M00003813D:C02 M00003875A:B01 M00004105C:B05M00003813D:G06 M00003875B:F12 M00004105C:C08 M00003814B:C01M00003875C:A01 M00004107A:A12 M00003817C:A10 M00003875C:A09M00004107B:D07 M00003817C:G06 M00003875C:G02 M00004108B:B02M00003817D:D12 M00003876B:C05 M00004108D:E07 M00003821A:H09M00003876C:D02 M00004108D:G04 M00003822B:G12 M00003876C:F02M00004110A:A10 M00003822C:A07 M00003877B:H10 M00004110B:A07M00003823C:B01 M00003868D:B09 M00004118B:A03 M00003823C:C04M00003871D:A10 M00004118B:F01 M00003824A:G11 M00001669D:D06M00004118D:B05 M00003824B:C09 M00001661A:B11 M00004119A:C09M00003824C:A10 M00001661B:F06 M00004136D:B02 M00003824D:D08M00001662A:C07 M00004137A:D06 M00003825B:F10 M00001662A:G01M00004139C:A12 M00003825D:F01 M00001662B:F06 M00004149C:B02M00003826C:F05 M00001663C:F12 M00004159C:G12 M00003829A:B08M00001664A:F08 M00004169D:B11 M00003829C:E08 M00001664D:F04M00004187D:H06 M00003829D:D12 M00001661A:E06 M00004228C:H03M00003829D:F03 M00001669A:B02 M00004244C:G07 M00003830D:B11M00001669B:B12 M00004358D:C02 M00003830D:H11 M00001669C:C08M00004690A:G08 M00003833D:H08 M00001675A:G10 M00004891B:D01M00003833D:H10 M00001669D:C03 M00004891C:D04 M00003840A:C10M00001660B:E03 M00004895B:E12 M00003840B:F05 M00001669D:F05M00004895B:G04 M00003840C:C02 M00001670B:G12 M00004895D:G07M00003845C:D04 M00001671A:A10 M00004898C:F03 M00003845D:A04M00001671B:G05 M00004899D:G06 M00003846B:C05 M00001671C:C11M00004959D:H12 M00003846C:F08 M00001672D:E08 M00004960A:B08M00003848B:E07 M00001673A:G08 M00004960C:E10 M00003848D:G02M00001673B:B07 M00005100A:B02 M00003850C:G09 M00001673B:F07M00005100A:C01 M00003851A:A06 M00001673D:D06 M00005101C:E12M00003851B:D03 M00001673D:F10 M00005102C:D03 M00003851B:E01M00001674A:G07 M00005134B:E08 M00003851C:F09 M00001692D:B01M00005139A:H03 M00003851D:H11 M00001669C:D09 M00005140C:B10M00003852B:G04 M00001655C:E01 M00005140D:C06 M00003852C:F07M00001649D:A08 M00005178D:H04 M00003853B:C10 M00001650A:C11M00005210A:E06 M00003854C:C09 M00001651A:H11 M00005212B:E01M00003855A:A01 M00001652A:A01 M00005212C:C03 M00003855A:F01M00001652B:G10 M00005212C:D02 M00003855B:B09 M00001652D:E05M00005212C:H02 M00003856A:G04 M00001652D:E09 M00005212D:D09M00003856B:A12 M00001653B:C06 M00005212D:H01 M00003857A:E12M00001653B:G10 M00005216A:D09 M00003857A:H10 M00001653C:D10M00005216A:H01 M00003857C:E05 M00001654D:A03 M00005217B:A06M00003858B:G02 M00001654D:E12 M00005218A:F09 M00003860D:E06M00001654D:F11 M00005228A:B03 M00003905C:F12 M00001660C:B06M00005228C:C05 M00003911A:D12 M00001658D:G12 M00005229B:G12M00003966B:A04 M00001675C:A04 M00005229B:H04 M00003966C:A12M00001660B:D03 M00005229B:H06 M00003966C:F03 M00001660B:A09M00005229D:H03 M00003973D:F08 M00001659D:C09 M00005230B:H09M00003974D:E01 M00001659D:B05 M00005232A:H12 M00003974D:H07M00001654D:F12 M00005233B:D04 M00003976B:E06 M00001659A:D12M00005233D:H07 M00003976B:H07 M00001655A:B11 M00005235B:F10M00003978A:E01 M00001658B:A07 M00005236A:E04 M00003978A:E09M00001658A:G09 M00005236A:G10 M00003978C:A12 M00001657D:A04M00005236B:A12 M00003980C:E12 M00001657B:B04 M00001448B:A07M00003980C:F12 M00001656B:E01 M00001448B:G07 M00003981A:A07M00001660B:E04 M00001448D:E11 M00003981B:B12 M00001659C:F10M00001455A:D10 M00003982A:G03 M00003808C:A05 M00001455A:E11M00003982B:C10 M00001694D:C12 M00001476D:F12 M00003982B:H10M00003746C:E02 M00001478A:F12 M00003983A:D02 M00003779D:E08M00001482C:F09 M00003983A:F06 M00003792A:B10 M00001485C:D07M00003983A:G02 M00003793D:A11 M00001485C:G06 M00003983D:E08M00003794D:G03 M00001485D:A05 M00003983D:H02 M00003797A:C11M00001487C:A11 M00003985A:C01 M00003797A:D06 M00001487C:G09M00003986C:G11 M00003797A:G03 M00001530A:B02 M00003986D:H12M00003800B:F03 M00001530A:H05 M00004027A:A08 M00003805A:F02M00001530D:A11 M00004028A:B10 M00003806B:C09 M00001539B:B10M00004028A:G03 M00001674A:G11 M00001567A:C04 M00004029B:A01M00003806D:D11 M00001567A:C11 M00004029B:A06 M00001693D:E08M00001567C:B08 M00004029B:G10 M00003808D:D08 M00001567C:E07M00004029C:F02 M00003809A:C01 M00001570C:B02 M00004029C:F05M00003809A:F01 M00001570D:E05 M00004030B:A12 M00003809B:B02M00001570D:E07 M00004030B:D08 M00003809B:E10 M00001573B:A06M00004030C:A08 M00003813A:B02 M00001573B:H12 M00004030C:C02M00003813A:D08 M00001575A:D05 M00004034C:F05 M00003813B:E09M00001575B:C01 M00004035B:F05 M00003814B:C12 M00001576C:H02M00004036A:A11 M00003814B:F12 M00001577A:A03 M00004037C:D04M00003815C:C06 M00001578B:A06 M00004038A:E05 M00003815C:D12M00001579D:F02 M00004038B:D01 M00003817B:C04 M00001582C:C04M00004039C:E02 M00003806B:G05 M00001582C:G02 M00004039D:B10M00001679A:D10 M00001584A:A07 M00004040A:A07 M00001675C:C03M00001584D:B06 M00004040A:B04 M00001675C:D12 M00001584D:C11M00004040A:C08 M00001675D:E10 M00001585D:B12 M00004040B:C05M00001676B:B09 M00001586C:H07 M00004040B:F07 M00001676B:E01M00001589D:A01 M00004069A:E12 M00001676C:A04 M00001590D:B04M00004069C:C08 M00001676C:E07 M00001592B:B02 M00004077A:G12M00001676D:A02 M00001592D:H02 M00004085B:G01 M00001676D:B02M00001594C:E05 M00004087A:B05 M00001677A:G11 M00001594C:H03M00004090D:F12 M00001677B:A12 M00001594D:G11 M00004092C:D08M00001677B:B04 M00001595A:C07 M00004097C:E03 M00001677D:B01M00001595A:D12 M00004097C:H08 M00001678D:B11 M00001595A:E07M00004097D:B05 M00001681C:A08 M00001595B:G07 M00003819B:G01M00001595B:G10 M00001693C:E09 M00001595B:H11 M00001693C:C12M00001595C:A01 M00001692B:E01 M00001595C:A05 M00001692A:B06M00001595C:B12 M00001678B:H01 M00001595C:E05 M00001681D:C12M00001595C:E09 M00001694A:E03 M00001595D:C11 M00001680B:D02M00001596A:A02 M00001680A:B02 M00001596A:D01 M00001679D:F02M00001596C:G05 M00001679D:B02 M00001607A:A01 M00001679A:G06Retrieval of Individual Clones from Deposit of Pooled Clones

Where the ATCC deposit is composed of a pool of cDNA clones, the depositwas prepared by first transfecting each of the clones into separatebacterial cells. The clones were then deposited as a pool of equalmixtures in the composite deposit. Particular clones can be obtainedfrom the composite deposit using methods well known in the art. Forexample, a bacterial cell containing a particular clone can beidentified by isolating single colonies, and identifying coloniescontaining the specific clone through standard colony hybridizationtechniques, using an oligonucleotide probe or probes designed tospecifically hybridize to a sequence of the clone insert (e.g., a probebased upon unmasked sequence of the encoded polynucleotide having theindicated SEQ ID NO). The probe should be designed to have a T_(m) ofapproximately 80° C. (assuming 2° C. for each A or T and 4° C. for eachG or C). Positive colonies can then be picked, grown in culture, and therecombinant clone isolated. Alternatively, probes designed in thismanner can be used to PCR to isolate a nucleic acid molecule from thepooled clones according to methods well known in the art, e.g., bypurifying the cDNA from the deposited culture pool, and using the probesin PCR reactions to produce an amplified product having thecorresponding desired polynucleotide sequence.

Example 27 Source of Biological Materials and Overview of NovelPolynucleotides Expressed by the Biological Materials

cDNA libraries were constructed from either human colon cancer cell lineKm12L4-A (Morikawa, et al., Cancer Research (1988) 48:6863), KM12C(Morikawa et al. Cancer Res. (1988)48:1943-1948), or MDA-MB-231(Brinkley et al. Cancer Res. (1980) 40:3118-3129) was used to constructa cDNA library from mRNA isolated from the cells. Sequences expressed bythese cell lines were isolated and analyzed; most sequences were about275-300 nucleotides in length. The KM12L4-A cell line is derived fromthe KM12C cell line. The KM12C cell line, which is poorly metastatic(low metastatic) was established in culture from a Dukes' stage B₂surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). TheKML4-A is a highly metastatic subline derived from KM12C (Yeatman et al.Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am.Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived celllines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as amodel cell line for the study of colon cancer (see, e.g., Moriakawa etal., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman etal., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246).The MDA-MB-231 cell line was originally isolated from pleural effusions(Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastaticpotential, and forms poorly differentiated adenocarcinoma grade II innude mice consistent with breast carcinoma.

The sequences of the isolated polynucleotides were first masked toeliminate low complexity sequences using the XBLAST masking program(Claverie “Effective Large-Scale Sequence Similarity Searches,” In:Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed.,Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); seeparticularly Claverie, in “Automated DNA Sequencing and AnalysisTechniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, SanDiego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally,masking does not influence the final search results, except to eliminatesequences of relative little interest due to their low complexity, andto eliminate multiple “hits” based on similarity to repetitive regionscommon to multiple sequences, e.g., Alu repeats. Masking resulted in theelimination of 43 sequences. The remaining sequences were then used in aBLASTN vs. GenBank search; sequences that exhibited greater than 70%overlap, 99% identity, and a p value of less than 1×10⁻⁴⁰ werediscarded. Sequences from this search also were discarded if theinclusive parameters were met, but the sequence was ribosomal orvector-derived.

The resulting sequences from the previous search were classified intothree groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP(non-redundant proteins) database search: (1) unknown (no hits in theGenBank search), (2) weak similarity (greater than 45% identity and pvalue of less than 1×10⁻⁵), and (3) high similarity (greater than 60%overlap, greater than 80% identity, and p value less than 1×10⁻⁵).Sequences having greater than 70% overlap, greater than 99% identity,and p value of less than 1×10⁻⁴⁰ were discarded.

The remaining sequences were classified as unknown (no hits), weaksimilarity, and high similarity (parameters as above). Two searches wereperformed on these sequences. First, a BLAST vs. EST database search wasperformed and sequences with greater than 99% overlap, greater than 99%similarity and a p value of less than 1×10⁻⁴⁰ were discarded. Sequenceswith a p value of less than 1×10⁻⁶⁵ when compared to a database sequenceof human origin were also excluded. Second, a BLASTN vs. Patent GeneSeqdatabase was performed and sequences having greater than 99% identity, pvalue less than 1×10⁻⁴⁰, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rulesand redundancies in the dataset. Sequences with a p value of less than1×10⁻¹¹¹ in relation to a database sequence of human origin werespecifically excluded. The final result provided the 1,565 sequenceslisted as SEQ ID NOS:6097-7661 in the accompanying Sequence Listing andsummarized in Table 41A (inserted prior to claims). Each identifiedpolynucleotide represents sequence from at least a partial mRNAtranscript.

Table 41A provides: 1) the SEQ ID NO assigned to each sequence for usein the present specification; 2) the filing date of the U.S. priorityapplication in which the sequence was first filed; 3) the attorneydocket number assigned to the priority application (for internal use);4) the SEQ ID NO assigned to the sequence in the priority application;5) the sequence name used as an internal identifier of the sequence; and6) the name assigned to the clone from which the sequence was isolated.Because the provided polynucleotides represent partial mRNA transcripts,two or more polynucleotides of the invention may represent differentregions of the same mRNA transcript and the same gene. Thus, if two ormore SEQ ID NOS: are identified as belonging to the same clone, theneither sequence can be used to obtain the full-length mRNA or gene.

In order to confirm the sequences of SEQ ID NOS: 6097-7661, the cloneswere retrieved from a library using a robotic retrieval system, and theinserts of the retrieved clones re-sequenced. These “validation”sequences are provided as SEQ ID NOS:7662-8706 in the Sequence Listing,and a summary of the “validation” sequences provided in Table 41B(inserted prior to claims). Table 41B provides: 1) the SEQ ID NOassigned to each sequence for use in the present specification; 2) thesequence name assigned to the “validation” sequence obtained; 3) whetherthe “validation” sequence contains sequence that overlaps with anoriginal sequence of SEQ ID NOS: 6097-7661 (Validation Overlap (VO)), orwhether the “validation” sequence does not substantially overlap with anoriginal sequence of SEQ ID NOS: 6097-7661 (indicated by ValidationNon-Overlap (VNO)); and 4) where the sequence is indicated as VO, thename of the clone that contains the indicated “validation” sequence.“Validation” sequences are indicated as “VO” where the “validation”sequence overlaps with an original sequence (e.g., one of SEQ ID NOS:6097-7661), and/or the “validation” sequence belongs to the same clusteras the original sequence using the clustering technique described above.Because the inserts of the clones are generally longer than the originalsequence and the validation sequence, it is possible that a “validation”sequence can be obtained from the same clone as an original sequence butyet not share any of the sequence of the original. Such validationsequences will, however, belong to the same cluster as the originalsequence using the clustering technique described above. VO “validation”sequences are contained within the same clone as the original sequence(one of SEQ ID NOS: 6097-7661). “Validation” sequences that providedoverlapping sequence are indicating by “VO” can be correlated with theoriginal sequences they validate by referring to Table 41A. Sequencesindicated as VNO are treated as newly isolated sequences and may or maynot be related to the sequences of SEQ ID NOS: 6097-7661. Because the“validation” sequences are often longer than the original polynucleotidesequences and thus provide additional sequence information. Allvalidation sequences can be obtained either from an indicated clone(e.g., for VO sequences) or from a cDNA library described herein (e.g.,using primers designed from the sequence provided in the sequencelisting).

Example 28 Results of Public Database Search to Identify Function ofGene Products

SEQ ID NOS: 7662-8706 were translated in all three reading frames, andthe nucleotide sequences and translated amino acid sequences used asquery sequences to search for homologous sequences in either the GenBank(nucleotide sequences) or Non-Redundant Protein (amino acid sequences)databases. Query and individual sequences were aligned using the BLAST2.0 programs, available over the world wide web of the NCBI. (see alsoAltschul, et al. Nucleic Acids Res. (1997) 25:3389-3402). The sequenceswere masked to various extents to prevent searching of repetitivesequences or poly-A sequences, using the XBLAST program for masking lowcomplexity as described above.

Tables 41A and 41B (inserted before the claims) provide the alignmentsummaries having a p value of 1×10⁻² or less indicating substantialhomology between the sequences of the present invention and those of theindicated public databases. Table 41A provides the SEQ ID NO of thequery sequence, the accession number of the GenBank database entry ofthe homologous sequence, and the p value of the alignment. Table 41Aprovides the SEQ ID NO of the query sequence, the accession number ofthe Non-Redundant Protein database entry of the homologous sequence, andthe p value of the alignment. The alignments provided in Tables 41A and41B are the best available alignment to a DNA or amino acid sequence ata time just prior to filing of the present specification. The activityof the polypeptide encoded by the SEQ ID NOS listed in Tables 41A and41B can be extrapolated to be substantially the same or substantiallysimilar to the activity of the reported nearest neighbor or closelyrelated sequence. The accession number of the nearest neighbor isreported, providing a publicly available reference to the activities andfunctions exhibited by the nearest neighbor. The public informationregarding the activities and functions of each of the nearest neighborsequences is incorporated by reference in this application. Alsoincorporated by reference is all publicly available informationregarding the sequence, as well as the putative and actual activitiesand functions of the nearest neighbor sequences listed in Table 41 andtheir related sequences. The search program and database used for thealignment, as well as the calculation of the p value are also indicated.

Full length sequences or fragments of the polynucleotide sequences ofthe nearest neighbors can be used as probes and primers to identify andisolate the full length sequence of the corresponding polynucleotide.The nearest neighbors can indicate a tissue or cell type to be used toconstruct a library for the full-length sequences of the correspondingpolynucleotides. TABLE 41A Nearest Neighbor (BlastN vs. Genbank) SEQ IDACC'N DESCRIP. P VALUE 6667 L17043 Homo sapiens pregnancy-specificbeta-1-glycoprotein- 1.00E−12 11 gene. 6674 M18864 Rat bone protein I(BP-I) mRNA, partial cds. 7.00E−30 6705 L13838 Human genomic sequencefrom chromosome 13, 4.00E−36 clone ch13lambdacDNA17-18. 6714 U09646Human carnitine palmitoyltransferase II precursor 1.00E−34 6723 U72621Human LOT1 mRNA, complete cds 1.00E−43 6725 M20910 Human 7S L gene,complete. 1.00E−35 6732 Z48950 H. sapiens hH3.3B gene for histone H3.34.00E−36 6735 X00247 Human translocated c-myc gene in Raji Burkitt3.00E−44 lymphoma cells 6739 D80007 Human mRNA for KIAA0185 gene,partial cds 7.00E−52 6742 U14967 Human ribosomal protein L21 mRNA,complete cds. 2.00E−42 6745 M13934 Human ribosomal protein S14 gene,complete cds. 4.00E−45 6748 NM_003902.1 Homo sapiens far upstreamelement binding protein 1.00E−54 (FUBP) mRNA > :: gb|U05040|HSU05040Human FUSE binding protein mRNA, complete cds. 6753 L41142 Homo sapienssignal transducer and activator of 2.00E−62 transcription (STAT5) mRNA,complete cds. 6761 Z12112 pWE15A cosmid vector DNA 2.00E−52 6763 Z54386H. sapiens CpG island DNA genomic Msel fragment, 7.00E−48 clone 10g3,forward read cpg10g3.ft1a 6764 X80333 M. musculus rab18 mRNA 2.00E−526765 X52126 Human alternatively spliced c-myb mRNA 1.00E−64 6767 L26247Homo sapiens suilisol mRNA, complete cds. 3.00E−54 6772 NM_001736.1 Homosapiens complement component 5 receptor 1 4.00E−56 C5a anaphylatoxinreceptor mRNA, complete cds. 6773 Z50798 G. gallus mRNA for p52 4.00E−556775 AB002368 Human mRNA for KIAA0370 gene, partial cds 2.00E−58 6777M26697 Human nucleolar protein (B23) mRNA, complete cds. 4.00E−48 6779D42087 Human mRNA for KIAA0118 gene, partial cds 4.00E−56 6789 D50734Rat mRNA of antizyme inhibitor, complete cds 2.00E−50 6793 X02344 Homosapiens beta 2 gene 1.00E−67 6794 NM_001067.1 Homo sapiens topoisomerase(DNA) II alpha 7.00E−63 topoisomerase II (top2) mRNA, complete cds. 6797U36309 Gallus gallus rhoGap protein mRNA, complete cds 3.00E−62 6799NM_002842.1 Homo sapiens protein tyrosine phosphatase, receptor 2.00E−81type, H (PTPRH) mRNA > :: dbj|D15049|HUMSAP1C Human mRNA for proteintyrosine phosphatase 6803 U47322 Cloning vector DNA, complete sequence.1.00E−63 6810 NM_001190.1 Homo sapiens branched chain aminotransferase2, 4.00E−67 mitochondrial (BCAT2) mRNA > :: gb|U68418|HSU68418 Humanbranched chain aminotransferase precursor (BCATm) mRNA, nuclear geneencoding mitochondrial protein, complete cds 6814 S62077 HP1Hs alpha =25 kda chromosomal autoantigen 5.00E−68 [human, mRNA, 876 nt] 6815U34991 Human endogenous retrovirus clone c18.4, HERV- 2.00E−61 H/HERV-Ehybrid multiply spliced protease/integrase mRNA, complete cds, andenvelope protein mRNA, partial cds 6818 U18671 Human Stat2 gene,complete cds. 4.00E−77 6819 L18964 Human protein kinase C iota isoform(PRKCI) 4.00E−68 mRNA, complete cds. 6820 D29956 Human mRNA for KIAA0055gene, complete cds 6.00E−70 6821 M77140 H. sapiens pro-galanin mRNA, 3′end. 2.00E−72 6824 U51432 Homo sapiens nuclear protein Skip mRNA,complete 1.00E−75 cds 6825 M84334 Macacca mulatta hnRNP A1-gamma isoformmRNA, 5.00E−50 complete cds. 6826 NM_002592.1 Homo sapiens proliferatingcell nuclear antigen 1.00E−74 (PCNA) mRNA > :: gb|M15796|HUMCYL Humancyclin protein gene, complete cds. 6827 M88458 Human ELP-1 mRNAsequence. 4.00E−76 6828 U44940 Mus musculus quaking type I (QKI) mRNA,complete 2.00E−69 cds 6829 D17577 Mouse mRNA for kinesin-like protein(Kif1b), 2.00E−71 complete cds 6830 U18920 Human chromosome 17q12-21mRNA, clone pOV-3, 2.00E−72 partial cds. 6832 M21188 Humaninsulin-degrading enzyme (IDE) mRNA, 7.00E−82 complete cds. 6833 U49058Rattus norvegicus CTD-binding SR-like protein rA4 1.00E−67 mRNA, partialcds 6835 D10630 Mus musculus mRNA for zinc finger protein, 4.00E−76complete cds, clone: CTfin51 6836 U29156 Mus musculus eps15R mRNA,complete cds. 3.00E−84 6837 Y08135 M. musculus mRNA for ASM-likephosphodiesterase 1.00E−86 3a 6838 U90567 Gallus gallus glutamine richprotein mRNA, partial 5.00E−58 cds 6839 U58280 Mus musculus secondlargest subunit of RNA 4.00E−77 polymerase I (RPA2) mRNA, complete cds6840 S79539 Pat-12 = Pat-12 product [mice, embryonic stem ES 9.00E−84cells, mRNA, 2781 nt] 6841 D30666 Rat mRNA for brain acyl-CoA synthetaseII, complete 2.00E−89 cds 6842 U29156 Mus musculus eps15R mRNA, completecds. 2.00E−92 6844 U36909 Bos taurus Rho-associated kinase mRNA,complete e−104 cds 6845 L36315 Mus musculus (clone pMLZ-1) zinc fingerprotein e−105 6846 X80169 M. musculus mRNA for 200 kD protein e−106 6847X83577 M. musculus mRNA for K-glypican e−107 7156 Z95437 Human DNAsequence from cosmid A1 on 8.00E−21 chromosome 6 contains ESTs. HERVlike retroviral sequence 7208 X69907 H. sapiens gene for mitochondrialATP synthase c 6.00E−07 subunit (P1 form) 7221 M19390 Bovineinterstitial retinol binding protein 8.00E−31 7252 U19247 Homo sapiensinterferon-gamma receptor alpha chain 7.00E−41 gene, exon 7 and completecds 7266 U20239 Mus musculus fibrosin mRNA, partial cds 5.00E−38 7267D26361 Human mRNA for KIAA0042 gene, complete cds 2.00E−41 7291NM_000694.1 Homo sapiens aldehyde dehydrogenase 7 (ALDH7) 1.00E−37mRNA > :: gb|U10868|HSU10868 Human aldehyde dehydrogenase ALDH7 mRNA,complete cds. 7292 U84404 Human E6-associated proteinE6-AP/ubiquitin-protein 1.00E−46 ligase (UBE3A) mRNA, alternativelyspliced, complete cds 7299 U51714 Human GPI protein p137 mRNA, partialsequence, 3′- 9.00E−53 UTR. 7300 U58884 Mus musculus SH3-containingprotein SH3P7 mRNA, 2.00E−49 complete cds. similar to Human Drebrin 7306X79067 H. sapiens ERF-1 mRNA 3′ end 2.00E−72 7308 U00946 Human cloneA9A2BRB5 (CAC)n/(GTG)n repeat- 3.00E−54 containing mRNA 7313 D11078 Homosapiens RGH2 gene, retrovirus-like element 6.00E−49 7315 U05989 Rattusnorvegicus clone par-4 induced by effectors of 3.00E−64 apoptosis mRNA,complete cds. 7316 U13185 Cloning vector pbetagal-Enhancer, complete3.00E−52 sequence. 7318 D87443 Human mRNA for KIAA0254 gene, completecds 8.00E−63 7321 U19867 Cloning vector pSPL3, exon splicing vector,complete 7.00E−72 sequence, HIV envelope protein gp 160 and beta-lactamase, complete cds. 7323 U04817 Human protein kinase PITSLRE alpha2-3 mRNA, 4.00E−57 complete cds. 7326 U03687 Photinus pyralis modifiedluciferase gene, complete 3.00E−62 cds, and pUC18 derived vector. 7327U27196 Gallus gallus zinc finger protein (Fzf-1) mRNA, 1.00E−66 completecds. 7331 X53586 Human mRNA for integrin alpha 6 2.00E−71 7332 J05016Human (clone pA3) protein disulfide isomerase 3.00E−67 related protein(ERp72) mRNA, complete cds. 7333 M86752 Human transformation-sensitiveprotein (IEF SSP 1.00E−66 3521) mRNA, complete cds. 7335 L19437 Humantransaldolase mRNA containing transposable 5.00E−70 element, completecds 7337 X90857 H. sapiens mRNA for-14 gene, containing globin 1.00E−74regulatory element 7338 NM_003980.1 Homo sapiens microtubule associatedprotein 7 9.00E−76 mRNA 7341 U17901 Rattus norvegicus phospholipaseA-2-activating 3.00E−75 protein (plap) mRNA, complete cds. 7342 S80632threonine, tyrosine phosphatase [human, brain, mRNA 2.00E−69 Partial,1236 nt] 7343 M76541 Human DNA-binding protein (NF-E1) mRNA, 2.00E−80complete cds. 7344 S55305 14-3-3 protein gamma subtype = putativeprotein kinase 7.00E−93 C regulatory protein [rats, brain, mRNA, 3410nt] > :: dbj|D17447|D17447 Rattus norvegicus mRNA for 14- 3-3 proteingamma-subtype, complete cds 7345 NM_002350.1 Homo sapiens v-yes-1Yamaguchi sarcoma viral 3.00E−86 related oncogene homolog (LYN) mRNA >:: gb|M16038|HUMLYN Human lyn mRNA encoding a tyrosine kinase. 7346Y10725 M. musculus mRNA for protein kinase KIS 4.00E−68 7347 U89931Cloning vector pTRE, complete sequence 3.00E−65 7348 Z46386 Bovineherpesvirus type 4 DNA for nonconserved 3.00E−73 region F (DN599 likestrain) 7349 L77599 Homo sapiens (clone SEL214) 17q YAC (303G8) 2.00E−69RNA. 7351 Y10746 H. sapiens mRNA for protein containing MBD 1 2.00E−797352 L77599 Homo sapiens (clone SEL214) 17q YAC (303G8) 2.00E−71 RNA.7353 Z57619 H. sapiens CpG island DNA genomic Mse1 fragment, 7.00E−72clone 187a6, forward read cpg187a6.ft1b 7354 U48807 Human MAP kinasephosphatase (MKP-2) mRNA, 3.00E−76 complete cds 7356 M27444 Bos taurus(clone pTKD7) dopamine and cyclic AMP- 4.00E−76 regulated neuronalphosphoprotein (DARPP-32) mRNA, complete cds. 7357 U37150 Bos tauruspeptide methionine sulfoxide reductase 5.00E−78 (msrA) mRNA, completecds 7358 U02435 Cloning vector pSVbeta, complete sequence 1.00E−77 7359U09662 Cloning vector pSEAP-Enhancer, complete sequence 4.00E−79 7360M99566 sCos cloning vector SfiI containing bacteriophage 1.00E−79promoters and flanking restriction sites in sCos vectors. 7362 Z12112pWE15A cosmid vector DNA 4.00E−80 7363 U55387 Cricetulus griseus SL15mRNA, complete cds 2.00E−82 7365 L14684 Rattus norvegicusnuclear-encoded mitochondrial 2.00E−91 elongation factor G mRNA,complete cds. 7366 U49057 Rattus norvegicus CTD-binding SR-like proteinrA9 7.00E−93 mRNA, complete cds 7367 U57368 Mus musculus EGF repeattransmembrane protein 4.00E−97 mRNA, complete cds. 7368 AF000938 Musmusculus RNA polymerase I largest subunit 8.00E−94 7370 X80169 M.musculus mRNA for 200 kD protein e−102 7371 U09874 Mus musculus SKD3mRNA, complete cds. e−105 7372 D78020 Rat mRNA for NFI-A4, partial cdse−108 7611 Z73360 Human DNA sequence from cosmid 92M18, BRCA2 9.00E−22gene region chromosome 13q12-13 7618 X62078 H. sapiens mRNA for GM2activator protein 7.00E−72 7619 X85750 H. sapiens mRNA for transcriptassociated with 2.00E−50 monocyte to macrophage differentiation 7621X03473 Human gene for histone H1(0) 1.00E−67 7631 X64411 R. norvegicusmRNA for 100 kDa protein 1.00E−54 7634 X13345 Human gene for plasminogenactivator inhibitor 1 2.00E−59 7638 D86971 Human mRNA for KIAA0217 gene,partial cds 7.00E−83 7639 NM_001859.1 Homo sapiens solute carrier family31 7.00E−72 gb|U83460|HSU83460 Human high-affinity copper uptake protein(hCTR1) mRNA, complete cds 7640 X68194 H. sapiens h-Sp1 mRNA 5.00E−577641 AB002326 Human mRNA for KIAA0328 gene, partial cds 3.00E−74 7644D31762 Human mRNA for KIAA0057 gene, complete cds 3.00E−85 7646 X58472Mouse KIN17 mRNA for kin17 protein 2.00E−57 7647 U13185 Cloning vectorpbetagal-Enhancer, complete 2.00E−79 sequence. 7648 U55939 Expressionvector pVP-Nco, complete sequence. 1.00E−76 7649 D87671 Rattusnorvegicus mRNA for TIP120, complete cds 1.00E−87 7650 U25691 Musmusculus lymphocyte specific helicase mRNA, 4.00E−86 complete cds 7651U55939 Expression vector pVP-Nco, complete sequence. 5.00E−79 7652Z12112 pWE15A cosmid vector DNA 2.00E−79 7653 U13185 Cloning vectorpbetagal-Enhancer, complete 2.00E−79 sequence. 7654 U13185 Cloningvector pbetagal-Enhancer, complete 6.00E−80 sequence. 7655 Z12112 pWE15Acosmid vector DNA 6.00E−80 7656 U09661 Cloning vector pSEAP-Control,complete sequence 6.00E−80 7657 U36909 Bos taurus Rho-associated kinasemRNA, complete 2.00E−90 cds 7658 L36610 Mus musculus protein synthesisinitiation factor 4A 2.00E−71 (elF-4A) gene, exons 5, 6, 7, 8, and 9.7659 S79463 M-Sema F = a factor in neural network development 1.00E−857660 U35312 Mus musculus nuclear receptor co-repressor mRNA, 1.00E−98complete cds 7667 L32977 Homo sapiens (clone f17252) ubiquinolcytochrome c 0 reductase Rieske iron-sulphur protein (UQCRFS1) gene,exon 2 7672 S78454 Mus musculus metal response element DNA-binding 0protein M96 mRNA, complete cds 7682 M88458 Human ELP-1 mRNA sequence. 07718 S77512 LAMB2 = laminin beta 2 chain [human, placenta, e−131 mRNA,5642 nt] 7720 X53305 H. sapiens mRNA for stathmin 0 7721 J03591 HumanADP/ATP translocase mRNA, 3′ end, clone 0 pHAT3. 7726 L18964 Humanprotein kinase C iota isoform (PRKCI) 2E−67 mRNA, complete cds. 7736D29956 Human mRNA for KIAA0055 gene, complete cds 0 7745 M26697 Humannucleolar protein (B23) mRNA, complete cds. e−149 7765 U47322 Cloningvector DNA, complete sequence. 4E−65 7785 NM_002079.1 Homo sapiensglutamic-oxaloacetic transaminase 1, 0 soluble (aspartateaminotransferase 1) aspartate aminotransferase mRNA, complete cds. 7789U55939 Expression vector pVP-Nco, complete sequence. 2E−70 7790 D80007Human mRNA for KIAA0185 gene, partial cds 0 7791 NM_001904.1 Homosapiens catenin (cadherin-associated protein), e−108 beta 1 (88 kD)(CTNNB1) mRNA > :: emb|X87838|HSRNABECA H. sapiens mRNA for beta-catenin7797 U19867 Cloning vector pSPL3, exon splicing vector, complete 1E−44sequence, HIV envelope protein gp160 and beta- lactamase, complete cds.7798 M31061 Human ornithine decarboxylase gene, complete cds. 0 7817Z96177 H. sapiens telomeric DNA sequence, clone 2E−70 10QTEL040, read10QTELOO040.seq 7818 NM_001904.1 Homo sapiens catenin(cadherin-associated protein), e−176 beta 1 (88 kD) (CTNNB1) mRNA > ::emb|X87838|HSRNABECA H. sapiens mRNA for beta-catenin 7854 X83577 M.musculus mRNA for K-glypican 0 7857 S79539 Pat-12 = Pat-12 product[mice, embryonic stem ES e−176 cells, mRNA, 2781 nt] 7869 L38951 Homosapiens importin beta subunit mRNA, complete 1E−78 cds 7872 NM_003902.1Homo sapiens far upstream element binding protein 0 (FUBP) mRNA > ::gb|U05040|HSU05040 Human FUSE binding protein mRNA, complete cds. 7887L08783 BlueScribe M13 Plus cloning vector. 0 7905 U86751 Human nucleolarfibrillar center protein (ASE-1) 8E−95 mRNA, complete cds 7913 M21188Human insulin-degrading enzyme (IDE) mRNA, e−134 complete cds. 7927NM_001614.1 Homo sapiens actin, gamma 1 (ACTG1) mRNA > :: 0.00E+00emb|X04098|HSACTCGR Human mRNA for cytoskeletal gamma-actin 7932 U12404Human Csa-19 mRNA, complete cds. 0 7933 X79236 H. sapiens rps26 genee−145 7934 NM_003313.1 Homo sapiens tissue specific transplantationantigen 0 P35B (TSTA3) mRNA > :: gb|U58766|HSU58766 Human FX proteinmRNA, complete cds 7935 M27436 Human tissue factor gene, complete cds,with a Alu e−121 repetitive sequence in the 3′ untranslated region. > ::gb|I05724| Sequence 12 from Patent EP 0278776 7945 X79067 H. sapiensERF-1 mRNA 3′ end 0 7946 NM_003017.1 Homo sapiens splicing factor,arginine/serine-rich 3 e−135 (SFRS3) mRNA > :: gb|L10838|HUMSRP20 Homosapiens SR protein family, pre-mRNA splicing factor (SRp20) mRNA,complete cds. 7953 U48807 Human MAP kinase phosphatase (MKP-2) mRNA,0.00E+00 complete cds 7954 U48807 Human MAP kinase phosphatase (MKP-2)mRNA, 0.00E+00 complete cds 7969 U04817 Human protein kinase PITSLREalpha 2-3 mRNA, 8.00E−53 complete cds. 7972 U18297 Human MST1 (MST1)mRNA, complete cds. 0.00E+00 7973 NM_001859.1 Homo sapiens solutecarrier family 31 0 gb|U83460|HSU83460 Human high-affinity copper uptakeprotein (hCTR1) mRNA, complete cds 7985 X70272 single strandedreplicative centromeric Saccharomyces 3.00E−76 cerevisiae/E. colishuttle vector 7993 L26050 Human mitochondrial 2,4-dienoyl-CoA reductase0.00E+00 mRNA, complete cds. 7995 X06747 Human hnRNP core protein A1e−157 7997 M64571 Human microtubule-associated protein 4 mRNA, 0.00E+00complete cds. 8004 X65322.1 Cloning vector pCAT-Basic 9.00E−53 8009NM_002654.1 Homo sapiens pyruvate kinase, muscle (PKM2) e−159 mRNA > ::gb|M23725|HUMPKM2L Human M2- type pyruvate kinase mRNA, complete cds.8012 U49352 Human liver 2,4-dienoyl-CoA reductase mRNA, 2.00E−71complete cds 8022 D31889 Human mRNA for KIAA0072 gene, partial cds > ::e−167 gb|G27027|G27027 human STS SHGC-31585. 8037 U43944 Human breastcancer cytosolic NADP(+)-dependent 1.00E−89 malic enzyme mRNA, partialcds 8067 U83659 Human multidrug resistance-associated protein 3.00E−85homolog (MRP3) mRNA, partial cds 8092 M33519 Human HLA-B-associatedtranscript 3 (BAT3) 3.00E−84 mRNA, complete cds. 8093 U55387 Cricetulusgriseus SL15 mRNA, complete cds e−150 8114 L36315 Mus musculus (clonepMLZ-1) zinc finger protein e−162 8121 NM_003902.1 Homo sapiens farupstream element binding protein e−175 (FUBP) mRNA > ::gb|U05040|HSU05040 Human FUSE binding protein mRNA, complete cds. 8128X56932 H. sapiens mRNA for 23 kD highly basic protein 0.00E+00 8135X98654 H. sapiens mRNA for DRES9 protein 9.00E−97 8146 S62077 HP1Hsalpha = 25 kda chromosomal autoantigen 4.00E−68 [human, mRNA, 876 nt]8153 M23619 Human HMG-I protein isoform mRNA (HMGI gene), e−117 clone6A. 8173 NM_003217.1 Homo sapiens testis enhanced gene transcript 4E−998188 U18671 Human Stat2 gene, complete cds. 0.00E+00 8192 D43636 HumanmRNA for KIAA0096 gene, partial cds 0 8194 NM_002734.1 Homo sapiensprotein kinase, cAMP-dependent, 0 regulatory, type I, alpha (tissuespecific extinguisher 1) (PRKAR1A) mRNA > :: gb|M33336|HUMCAMPPK HumancAMP-dependent protein kinase type I-alpha subunit 8195 U72621 HumanLOT1 mRNA, complete cds 0.00E+00 8208 NM_003902.1 Homo sapiens farupstream element binding protein 0.00E+00 (FUBP) mRNA > ::gb|U05040|HSU05040 Human FUSE binding protein mRNA, complete cds. 8214L41142 Homo sapiens signal transducer and activator of 0.00E+00transcription (STAT5) mRNA, complete cds. 8215 Z48950 H. sapiens hH3.3Bgene for histone H3.3 0.00E+00 8249 L09260 Human (chromosome 3p25)membrane protein e−100 mRNA. 8254 X65304.1 Cloning vector pGEM-3Z e−1738259 NM_003358.1 Homo sapiens UDP-glucose ceramide e−141glucosyltransferase (UGCG) mRNA > :: dbj|D50840|HUMCGA Homo sapiens mRNAfor ceramide glucosyltransferase, complete cds > :: dbj|E12454|E12454cDNA encoding human ceramide glucosyltransferase 8275 M95605 Bos taurusS-adenosylmethionine decarboxylase e−175 8276 M12623 Human non-histonechromosomal protein HMG-17 0.00E+00 mRNA, complete cds. 8277 U79143Human phosphoinositide 3′-hydroxykinase p110-alpha 0.00E+00 subunitmRNA, complete cds 8288 K01906 Human fetal liver c-myc proto-oncogene,exon 3 and e−165 flanks. 8290 X74870 H. sapiens gene for RNA pol IIlargest subunit, exons e−161 23-29 8331 L16991 Human thymidylate kinase(CDC8) mRNA, complete 0.00E+00 cds. 8353 L08783 BlueScribe M13 Pluscloning vector. 0.00E+00 8372 NM_002245.1 Homo sapiens potassiuminwardly-rectifying channel, 0 subfamily K, member 1 (KCNK1) mRNA > ::gb|U33632|HSU33632 Human two P-domain K+ channel TWIK-1 mRNA, completecds. 8374 D50734 Rat mRNA of antizyme inhibitor, complete cds e−157 8375U26401 Human galactokinase (galK) mRNA, complete cds. > 0.00E+00 8381U49058 Rattus norvegicus CTD-binding SR-like protein rA4 e−138 mRNA,partial cds 8383 X65306.1 Cloning vector pGEM-3Zf(+) e−116 8395NM_001172.1 Homo sapiens arginase, type II (ARG2) mRNA > :: e−127gb|U82256|HSU82256 Homo sapiens arginase type II mRNA, complete cds 8405M25160 Human Na, K-ATPase beta subunit (ATP1B) gene, 0.00E+00 exons 3through 6. 8411 Y08736 H. sapiens vegf gene, 3′UTR 1.00E−78 8416 U13737Human cysteine protease CPP32 isoform alpha 0.00E+00 mRNA, complete cds.8419 Y08135 M. musculus mRNA for ASM-like phosphodiesterase e−148 3a8420 Y08135 M. musculus mRNA for ASM-like phosphodiesterase 0 3a 8424NM_001677.1 Homo sapiens ATPase, Na+/K+ transporting, beta 1 1E−77polypeptide (ATP1B1) mRNA > :: emb|X03747|HSATPBR Human mRNA for Na/K−ATPase beta subunit 8433 Y08135 M. musculus mRNA for ASM-likephosphodiesterase e−168 3a 8460 U54778 Human 14-3-3 epsilon mRNA,complete cds 1E−67 8461 Y08135 M. musculus mRNA for ASM-likephosphodiesterase 0 3a 8464 NM_001172.1 Homo sapiens arginase, type II(ARG2) mRNA > :: e−127 gb|U82256|HSU82256 Homo sapiens arginase type IImRNA, complete cds 8481 AB002293 Human mRNA for KIAA0295 gene, partialcds 0 8490 M21188 Human insulin-degrading enzyme (IDE) mRNA, 2E−81complete cds. 8521 D87466 Human mRNA for KIAA0276 gene, partial cds1E−97 8525 U58884 Mus musculus SH3-containing protein SH3P7 mRNA, 4E−96complete cds. similar to Human Drebrin 8537 AB005216 Homo sapiens mRNAfor Nck, Ash and phospholipase 0 C gamma-binding protein NAP4, partialcds 8538 NM_001960.1 Homo sapiens eukaryotic translation elongationfactor 0.00E+00 1 delta (guanine nucleotide exchange protein) (EEF1D)mRNA > :: emb|Z21507|HSEF1DELA H. sapiens EF-1delta gene encoding humanelongation factor-1-delta 8540 M92449 Human LTR mRNA, 3′ end of codingregion and 3′ e−143 flank. 8548 NM_003350.1 Homo sapiensubiquitin-conjugating enzyme E2 0 variant 2 (UBE2V2) mRNA > ::emb|X98091|HSVITDITR H. sapiens mRNA for protein induced by vitamin D8552 U44975 Homo sapiens DNA-binding protein CPBP (CPBP) 5.00E−69 mRNA,partial cds 8555 Z84510 H. sapiens flow-sorted chromosome 6 HindIII4.00E−66 fragment, SC6pA28B7 8559 Z48042 H. sapiens mRNA encodingGPI-anchored protein e−172 p137 8593 U32986 Human xeroderma pigmentosumgroup E UV- 0 damaged DNA binding factor mRNA, complete cds. 8611NM_003419.1 Homo sapiens zinc finger protein 10 (KOX 1) for zinc e−129finger protein 8616 Y00711 Human mRNA for lactate dehydrogenase B(LDH-B) 0.00E+00 8622 Y10725 M. musculus mRNA for protein kinase KIS0.00E+00 8639 X62078 H. sapiens mRNA for GM2 activator protein e−1648644 NM_001009.1 Homo sapiens ribosomal protein S5 (RPS5) mRNA 0.00E+00complete cds. 8652 U97188 Homo sapiens putative RNA binding protein KOC1E−86 8671 NM_002852.1 Homo sapiens pentaxin-related gene, rapidlyinduced 0.00E+00 by IL-1 beta (PTX3) mRNA > :: emb|X63613|HSPTX3R H.sapiens mRNA for pentaxin (PTX3) 8674 X67155 H. sapiens mRNA for mitotickinesin-like protein-1 0.00E+00 8684 M54968 Human K-ras oncogene proteinmRNA, complete cds> e−123 8687 D88687 Homo sapiens mRNA forKM-102-derived reductase- 0 like factor, complete cds 8689 NM_001436.1Homo sapiens fibrillarin (FBL) mRNA > :: e−103 gb|M59849|HUMFIBAA Humanfibrillarin (Hfib1) mRNA, complete cds. 8691 AB002326 Human mRNA forKIAA0328 gene, partial cds 0.00E+00 8694 M11948 Human promyelocyticleukemia cell mRNA, clones 9.00E−84 pHH58 and pHH81.

TABLE 41B Nearest Neighbor (BlastX vs. Non-Redundant Proteins) P SEQ IDACC'N DESCRIP. VALUE 6133 4239895 (AB016816) MASL1 [Homo sapiens]9.00E−54 6162 4514653 (AB024057) vascular Rab-GAP/TBC-containing6.00E−55 protein [Homo sapiens] 6174 4454524 (AC004841) similar toinsulin receptor substrate 6.00E−22 BAP2; similar to PID: g4126477 [Homosapiens] 6175 4545264 (AF118240) peroxisomal biogenesis factor 16 [Homo1.00E−45 sapiens] 6208 3413938 (AB007963) KIAA0494 protein [Homosapiens] 3.00E−44 6218 4239895 (AB016816) MASL1 [Homo sapiens] 1.00E−476235 4502371 breast cancer antiestrogen resistance 3 >gi|32373062.00E−44 (U92715) breast cancer antiestrogen resistance 3 protein [Homosapiens] 6250 4586880 (AB017114) AD 3 [Homo sapiens] 4.00E−48 62533327170 (AB014578) KIAA0678 protein [Homo sapiens] 2.00E−51 6264 3153241(AF053004) class I cytokine receptor [Homo sapiens] 2.00E−17 62674138233 (AJ007780) parp-2 gene [Mus musculus] 2.00E−32 6270 3287173(AJ006266) AND-1 protein [Homo sapiens] 2.00E−42 6283 4507145UNKNOWN >gi|3873216 (AF065485) sorting nexin 4 8.00E−46 [Homo sapiens]6303 4153860 (AC005074) similar to U47321 (PID: g1245146) 4.00E−15 [Homosapiens] 6320 3236430 (AF067379) ubiquitin-protein ligase E3-alpha [Mus3.00E−35 musculus] 6349 3043696 (AB011158) KIAA0586 protein [Homosapiens] 1.00E−44 6356 4519623 (AB017616) homologous to the yeast YGR163gene 2.00E−54 [Mus musculus] 6376 4455035 (AF116238) pseudouridinesynthase 1 [Homo sapiens] 4.00E−48 6400 3075377 (AC004602) F23487_2[Homo sapiens] 2.00E−21 6402 4505611 poly(A)-specific ribonuclease7.00E−41 6469 1825606 (U88169) similar to molybdoterin biosynthesis MOEB2.00E−37 proteins [Caenorhabditis elegans] 6478 4586287 (AB004794)DUF140 [Xenopus laevis] 7.00E−45 6492 3941342 (AF043250) mitochondrialouter membrane protein 5.00E−40 [Homo sapiens] >gi|3941347 (AF043253)mitochondrial outer membrane protein [Homosapiens] >gi|4105703|gb|AAD02504| 6510 4586844 (AB015633) type IImembrane protein 2.00E−46 6518 3327078 (AB014532) KIAA0632 protein [Homosapiens] 6.00E−36 6529 3327230 (AB014608) KIAA0708 protein [Homosapiens] 5.00E−52 6568 3372677 (AF061749) tumorous imaginal discsprotein Tid56 7.00E−35 homolog 6598 4050034 (AF098482) transcriptionalcoactivator p52 [Homo 1.00E−36 sapiens] 6600 4406632 (AF131801) Unknown[Homo sapiens] 3.00E−21 6608 3114828 (AJ005897) JM5 [Homo sapiens]3.00E−44 6626 3766209 (AF071777) IRE1 [Mus musculus] 2.00E−29 66573043644 (AB011132) KIAA0560 protein [Homo sapiens] 3.00E−43 6668 3088575(AF059531) protein arginine N-methyltransferase 3 4.00E−46 [Homosapiens] 6674 4505891 UNKNOWN >gi|3153235 (AF046889) lysyl 3.00E−30hydroxylase isoform 3 [Homo sapiens] >gi|3551836 6686 3114828 (AJ005897)JM5 [Homo sapiens] 1.00E−24 6688 3242214 (AJ006778) DRIM protein [Homosapiens] 2.00E−36 6694 4200236 (AL035308) hypothetical protein [Homosapiens] 8.00E−09 6696 3413892 (AB007934) KIAA0465 protein [Homosapiens] 2.00E−51 6731 3043626 (AB011123) KIAA0551 protein [Homosapiens] 3.00E−31 6739 2498864 RRP5 PROTEIN HOMOLOG (KIAA0185) 3.00E−13hypothetical protein YM9959.11C of S. cerevisiae. [Homo sapiens] 67663402197 (AJ010014) M96A protein [Homo sapiens] 1.00E−21 6773 2217964(Z50798) p52 [Gallus gallus] 7.00E−14 6782 3043626 (AB011123) KIAA0551protein [Homo sapiens] 1.00E−40 6793 135470 TUBULIN BETA-5 CHAINsapiens] 3.00E−21 6797 3327056 (AB014521) KIAA0621 protein [Homosapiens] 2.00E−29 6800 4506787 UNKNOWN GTPASE-ACTIVATING-LIKE 4.00E−41PROTEIN IQGAP1 (P195) (KIAA0051) protein -human >gi|473931|dbj|BAA06123| (D29640) KIAA0051 [Homosapiens] >gi|536844 (L33075) ras GTPase-activating-like protein [Homosapiens] 6805 1350762 60S RIBOSOMAL PROTEIN L6 sapiens] 2.00E−22 68092687400 (AF035824) vesicle soluble NSF attachment protein 1.00E−23receptor [Homo sapiens] 6826 2914385 Chain C, HumanPcna >gi|2914387|pdb|1AXC|E 2.00E−27 Chain E, Human Pcna 6827 284076ERD-2-like protein, ELP-1 - human 1.00E−26 6829 2497524 KINESIN-LIKEPROTEIN KIF1B mouse 9.00E−33 >gi|407339|dbj|BAA04503| (D17577) Kif1b[Mus musculus] 6831 3327056 (AB014521) KIAA0621 protein [Homo sapiens]1.00E−13 6832 279567 insulinase (EC 3.4.99.45) - human 2.00E−26 6834487416 (L20302) actin filament protein [Gallus gallus] 3.00E−45 68351731428 ZINC FINGER PROTEIN ZFP-38 7.00E−35 6836 968973 (U29156)involved in signaling by the epidermal 1.00E−22 growth factor receptor;Method: conceptual translation supplied by author. [Mus musculus] 68371552350 (Y08135) acid sphingomyelinase-like 2.00E−35 phosphodiesterase[Mus musculus] 6838 3327098 (AB014542) KIAA0642 protein [Homo sapiens]3.00E−15 6839 3914801 DNA-DIRECTED RNA POLYMERASE I 135 KD 2.00E−45POLYPEPTIDE (RNA POLYMERASE I SUBUNIT 2) (RPA135) (RNA POLYMERASE I 127KD SUBUNIT) >gi|2739048 (AF025424) RNA polymerase I 127 kDa subunit[Rattus norvegicus] 6841 4165018 (D89053) Acyl-CoA synthetase 3 [Homosapiens] 2.00E−53 6842 968973 (U29156) involved in signaling by theepidermal 3.00E−40 growth factor receptor; Method: conceptualtranslation supplied by author. [Mus musculus] 6843 4519883 (AB017970)dipeptidyl peptidase III 4.00E−50 6844 3327052 (AB014519) KIAA0619protein [Homo sapiens] 7.00E−30 6845 538413 (L36315) zinc finger protein[Mus musculus] 6.00E−55 6846 1717793 PROTEIN TSG24 (MEIOTIC CHECK POINT1.00E−50 REGULATOR) >gi|1083553|pir||A55117 tsg24 protein - mouse 68473420277 (AF064826) glypican 4 [Homo sapiens] 3.00E−54 6904 4580645(AF118855) trans-prenyltransferase [Mus musculus] 2.00E−48 6925 3882171(AB018268) KIAA0725 protein [Homo sapiens] 3.00E−24 6929 4104976(AF043117) ubiquitin-fusion degradation protein 2 2.00E−41 [Homosapiens] 6937 3242214 (AJ006778) DRIM protein [Homo sapiens] 4.00E−347010 4191810 (AB006532) DNA helicase [Homo sapiens] 5.00E−41 70553043714 (AB011167) KIAA0595 protein [Homo sapiens] 5.00E−20 7078 4379097(Y17999) Dyrkl B protein kinase [Homo sapiens] 3.00E−21 7124 3043712(AB011166) KIAA0594 protein [Homo sapiens] 2.00E−49 7175 4240227(AB020676) KIAA0869 protein [Homo sapiens] 4.00E−35 7187 4235226(AF061025) leucine zipper-EF-hand containing 6.00E−34 transmembraneprotein 1 [Homo sapiens] 7230 3426268 (AF044201) neural membrane protein35; NMP35 1.00E−29 [Rattus norvegicus] 7248 4507367 threonyl-tRNAsynthetase SYNTHETASE, 3.00E−26 CYTOPLASMIC (THREONINE--TRNA LIGASE)(THRRS) 6.1.1.3) - human >gi|1464742 (M63180) threonyl-tRNA synthetase[Homo sapiens] 7249 2072294 (U95097) mitotic phosphoprotein 43 [Xenopuslaevis] 1.00E−19 7259 543222 glutamine (Q)-rich factor 1, QRF-1 - mousefactor 1, 1.00E−39 QRF-1 [mice, B-cell leukemia, BCL1, Peptide Partial,84 aa] 7260 3335569 (AF072759) fatty acid transport protein 4; FATP47.00E−39 [Mus musculus] 7264 2996194 (AF053232) SIK similar protein [Musmusculus] 1.00E−31 7268 2935597 (AC004262) R29368_2 [Homo sapiens]6.00E−49 7297 2645205 (U63648) p160 myb-binding protein [Mus musculus]1.00E−21 7300 1407655 (U58884) SH3P7 [Mus musculus] 8.00E−21 73102134381 polybromo 1 protein - chicken 8.00E−29 7315 4505613 PRKC,apoptosis, WT1, regulator par-4 [Homo 6.00E−34 sapiens] 7325 3757892(AF079765) enhancer of polycomb [Mus musculus] 3.00E−41 7327 2134436zinc finger protein - chicken (fragment) 4.00E−37 7328 2393722 (U90313)glutathione-S-transferase homolog [Homo 6.00E−34 sapiens] 7330 459002(U00036) R151.6 gene product [Caenorhabditis 7.00E−10 elegans] 7332119530 PROTEIN DISULFIDE ISOMERASE-RELATED 3.00E−23 PROTEIN PRECURSOR(ERP72) >gi|87320|pir||A23723 protein disulfide-isomerase (EC 5.3.4.1)ERp72 precursor - human protein [Homo sapiens] 7335 2073541 (L19437)transaldolase [Homo sapiens] >gi|2612879 2.00E−24 7337 984125 (X90857) -14 [Homo sapiens] 2.00E−23 7341 4106818 (AF083395) phospholipaseA2-activating protein 4.00E−36 [Homo sapiens] 7343 4507955 YY1transcription factor REPRESSOR PROTEIN 4.00E−27 YY1 (YIN AND YANG 1)(YY-1) (DELTA TRANSCRIPTION FACTOR) (NF-E1) >gi|38011|emb|CAA78455| 73461698779 (U70372) PAM COOH-terminal interactor protein 2 6.00E−35 [Rattusnorvegicus] 7348 4204684 (AF102542)beta-1,6-N-acetylglucosaminyltransferase 9.00E−43 core 2/core 4beta-1,6-N- acetylglucosaminyltransferase; core 2/4-GnT [Homo sapiens]7351 2239126 (Y10746) methyl-CpG binding protein [Homo sapiens] 4.00E−167355 1747519 (U76759) nuclear protein NIP45 [Mus musculus] 2.00E−29 7356545790 DARPP-32 = dopamine and cAMP-regulated 1.00E−29 phosphoprotein[human, brain, Peptide, 204 aa] sapiens] 7357 1709689 PEPTIDE METHIONINESULFOXIDE 1.00E−37 REDUCTASE (PEPTIDE MET(O) REDUCTASE) >gi|1205993taurus] 7361 2736151 (AF021935) mytonic dystrophy kinase-related Cdc42-1.00E−41 binding kinase [Rattus norvegicus] 7363 3329392 (AF038961) SL15protein [Homo sapiens] 8.00E−36 7364 4097712 (U67322) HBV associatedfactor [Homo sapiens] 7.00E−56 7365 585084 ELONGATION FACTOR G,MITOCHONDRIAL 7.00E−49 PRECURSOR (MEF-G) >gi|543383|pir||S40780translation elongation factor G, mitochondrial - rat >gi|310102 73661438534 (U49057) rA9 [Rattus norvegicus] 3.00E−45 7367 1336628 (U57368)EGF repeat transmembrane protein [Mus 7.00E−47 musculus] 7368 3914802DNA-DIRECTED RNA POLYMERASE I LARGEST 1.00E−37 SUBUNIT (RNA POLYMERASE I194 KD SUBUNIT) (RPA194) 7369 3387977 (AF070598) ABC transporter [Homosapiens] 5.00E−50 7370 1717793 PROTEIN TSG24 (MEIOTIC CHECK POINT2.00E−48 REGULATOR) >gi|1083553|pir||A55117 tsg24 protein - mouse 73712493735 SKD3 PROTEIN SKD3 [Mus musculus] 7.00E−43 7372 1041038 (D78020)NFI-A4 [Rattus norvegicus] 3.00E−26 7380 4455118 (AF125158) zinc fingerDNA binding protein 99 9.00E−41 7418 4049922 (AF072810) transcriptionfactor WSTF [Homo 4.00E−48 sapiens] 7434 4586287 (AB004794) DUF140[Xenopus laevis] 3.00E−45 7441 3435244 (AF083322) centriole associatedprotein CEP110 2.00E−40 [Homo sapiens] 7466 3413886 (AB007931) KIAA0462protein [Homo sapiens] 2.00E−35 7558 3882311 (AB018338) KIAA0795 protein[Homo sapiens] 4.00E−47 7593 4240167 (AB020646) KIAA0839 protein [Homosapiens] 2.00E−46 7613 4191610 (AF117107) IGF-II mRNA-binding protein 2[Homo 3.00E−49 sapiens] 7615 3135669 (AF064084) prenylcysteine carboxylmethyltransferase 1.00E−39 7625 3043548 (AB011084) KIAA0512 protein[Homo sapiens] 2.00E−47 7627 3093476 (AF008915) EVI-5 homolog [Homosapiens] 6.00E−19 7628 3834629 (AF094519) diaphanous-related formin;p134 mDia2 1.00E−32 [Mus musculus] 7629 3193226 (AF068706)gamma2-adaptin [Homo sapiens] 1.00E−46 7630 3851584 (AF092563)chromosome-associated protein-E [Homo 4.00E−48 sapiens] 7631 4101695(AF006010) progestin induced protein [Homo sapiens] 5.00E−30 76463850704 (AJ005273) Kin17 [Homo sapiens] 9.00E−24 7649 4240147 (AB020636)KIAA0829 protein [Homo sapiens] 9.00E−41 7650 2137490 lymphocytespecific helicase - mouse musculus] 5.00E−35 7657 3327052 (AB014519)KIAA0619 protein [Homo sapiens] 1.00E−41 7659 2137494 M-sema F proteinprecusor - mouse F [mice, neonatal 7.00E−34 brain, Peptide, 834 aa] [Mussp.] 7660 2137603 nuclear receptor co-repressor N-CoR - mouse 9.00E−41musculus] >gi|1583865|prf||2121436A thyroid hormone receptorco-repressor [Mus musculus] 7661 2674107 (AF023451) guaninenucleotide-exchange protein [Bos 3.00E−48 taurus] 7683 3659505(AC005084) similar to mouse mCASK-A; similar to 1.00E−57 e1288039 7745114762 NUCLEOPHOSMIN (NPM) (NUCLEOLAR 6.00E−35 PHOSPHOPROTEIN B23)(NUMATRIN) (NUCLEOLAR PROTEIN NO38) sapiens] 7747 3327056 (AB014521)KIAA0621 protein [Homo sapiens] 8.00E−40 7784 4545264 (AF118240)peroxisomal biogenesis factor 16 [Homo 2.00E−65 sapiens] 7790 2498864RRP5 PROTEIN HOMOLOG (KIAA0185) 7.00E−77 hypothetical protein YM9959.11Cof S. cerevisiae. [Homo sapiens] 7854 3420277 (AF064826) glypican 4[Homo sapiens] 4.00E−76 7864 3088575 (AF059531) protein arginineN-methyltransferase 3 7.00E−97 [Homo sapiens] 7867 4050034 (AF098482)transcriptional coactivator p52 [Homo 2.00E−58 sapiens] 7907 4506357UNKNOWN; PZR >gi|3851145 sapiens] 2.00E−60 7926 3387977 (AF070598) ABCtransporter [Homo sapiens] e−113 7932 1709974 60S RIBOSOMAL PROTEIN L10Aprotein L10a e−111 [Rattus norvegicus] Ribosomal Protein RPL10A) [Homosapiens] 7934 4507709 tissue specific transplantation antigen P35B9.00E−90 >gi|1381179 (U58766) FX [Homo sapiens] 7972 1117791 (U18297)MST1 [Homo sapiens] 4E−85 7973 4507015 copper transporter 1 3.00E−727993 4503301 2,4-dienoyl CoA reductase REDUCTASE, 6E−94 MITOCHONDRIALPRECURSOR (2,4-DIENOYL- COA REDUCTASE (NADPH)) (4-ENOYL-COA REDUCTASE(NADPH)) precursor, mitochondrial - human >gi|602703 (L26050)2,4-dienoyl-CoA reductase [Homo sapiens] >gi|2673979 precursor [Homosapiens] >gi|4126313 (AF049895) 2,4-dienoyl- CoA reductase [Homosapiens] 7997 126743 MICROTUBULE-ASSOCIATED PROTEIN 4 human6E−84 >gi|187383 (M64571) microtubule-associated protein 4 [Homosapiens] 8010 4505987 PTPRF interacting protein, binding protein 1(liprin 4E−89 beta 1) >gi|3309539 (AF034802) liprin-beta1 [Homo sapiens]8016 3043644 (AB011132) KIAA0560 protein [Homo sapiens] e−108 80403413892 (AB007934) KIAA0465 protein [Homo sapiens] 7.00E−87 8052 4185796(AF103796) placenta-specific ATP-binding cassette 2E−68 transporter[Homo sapiens] 8069 4507145 UNKNOWN >gi|3873216 (AF065485) sorting nexin4 1.00E−73 [Homo sapiens] 8104 1083566 zinc fingerprotein/transactivator Zfp-38 - mouse2E−64 >gi|55477|emb|CAA45280|(X63747) Zfp-38 [Mus musculus] 8114 1806134(Z67747) zinc finger protein [Mus musculus] 7.00E−78 8128 730451 60SRIBOSOMAL PROTEIN L13A (23 KD HIGHLY 4.00E−87 BASICPROTEIN) >gi|345897|pir||S29539 basic protein, 23 K -human >gi|23691|emb|CAA40254| (X56932) 23 kD highly basic protein [Homosapiens] 8381 4102967 (AF023142) pre-mRNA splicing SR protein rA41.00E−33 [Homo sapiens] 8413 3108093 (AF061258) LIM protein [Homosapiens] 6.00E−82 8414 3170887 (AF061555) ubiquitin-protein ligaseE3-alpha [Mus e−104 musculus] 8420 1552350 (Y08135) acidsphingomyelinase-like 6.00E−91 phosphodiesterase [Mus musculus] 84611552350 (Y08135) acid sphingomyelinase-like e−106 phosphodiesterase [Musmusculus] 8462 3242214 (AJ006778) DRIM protein [Homo sapiens] e−114 84834514653 (AB024057) vascular Rab-GAP/TBC-containing e−121 protein [Homosapiens] 8537 2443367 (AB005216) Nck, Ash and phospholipase C gamma-e−120 binding protein NAP4 [Homo sapiens] 8571 119110 EBNA-1 NUCLEARPROTEIN herpesvirus 4 (strain 2.00E−38B95-8) >gi|1334880|emb|CAA24816.1|gene. [Human herpesvirus 4] 8575121640 GLYCINE-RICH CELL WALL STRUCTURAL 8.00E−31 PROTEINPRECURSOR >gi|72320|pir||KNMU glycine-rich cell wall protein precursor -Arabidopsis thaliana 8591 1362077 glycin-rich protein - cowpea(fragment) 2E−40 8615 121640 GLYCINE-RICH CELL WALL STRUCTURAL 9.00E−27PROTEIN PRECURSOR >gi|72320|pir||KNMU glycine-rich cell wall proteinprecursor - Arabidopsis thaliana 8642 2674107 (AF023451) guaninenucleotide-exchange protein [Bos 5E−89 taurus] 8644 3717978 (Y12431) 5Sribosomal protein [Mus musculus] 5E−94 8652 4191610 (AF117107) IGF-IImRNA-binding protein 2 [Homo e−111 sapiens] 8674 2119281 CHO1 antigen -Chinese hamster e−101 8675 3435244 (AF083322) centriole associatedprotein CEP110 2E−70 [Homo sapiens] 8687 1843434 (D88687) KM-102-derivedreductase-like factor 4.00E−91 [Homo sapiens] 8700 3834629 (AF094519)diaphanous-related formin; p134 mDia2 1E−49 [Mus musculus]

Example 29 Members of Protein Families

SEQ ID NOS: 7662-8706 were used to conduct a profile search as describedin the specification above. Several of the polynucleotides of theinvention were found to encode polypeptides having characteristics of apolypeptide belonging to a known protein family (and thus represent newmembers of these protein families) and/or comprising a known functionaldomain (Table 42A, inserted prior to claims). Table 42A provides the SEQID NO: of the query sequence, a brief description of the profile hit,the position of the query sequence within the individual sequence(indicated as “start” and “stop”), and the orientation (Direction) ofthe query sequence with respect to the individual sequence, whereforward (for) indicates that the alignment is in the same direction(left to right) as the sequence provided in the Sequence Listing andreverse (rev) indicates that the alignment is with a sequencecomplementary to the sequence provided in the Sequence Listing. TABLE42A Profile Hits SEQ ID NO: Description Start Stop Dir 8063 14_3_3proteins 166 845 for 8462 3′5′-cyclic nucleotide phosphodiesterases 64573 for 7675 4 transmembrane integral membrane 300 924 rev proteins 80744 transmembrane integral membrane 340 941 rev proteins 7748 7transmembrane receptor (rhodopsin 109 647 rev family) 8023 7transmembrane receptor (rhodopsin 84 947 rev family) 8164 7transmembrane receptor (rhodopsin 305 975 for family) 7694 7transmembrane receptor (Secretin 50 1269 for family) 7815 7transmembrane receptor (Secretin 63 1160 rev family) 8007 7transmembrane receptor (Secretin 38 869 rev family) 8023 7 transmembranereceptor (Secretin 237 930 rev family) 8164 7 transmembrane receptor(Secretin 188 975 for family) 8437 7 transmembrane receptor (Secretin377 1524 rev family) 7767 ATPases Associated with Various 136 718 forCellular Activities 7768 ATPases Associated with Various 271 765 forCellular Activities 7784 ATPases Associated with Various 206 709 revCellular Activities 7892 ATPases Associated with Various 139 783 forCellular Activities 7926 ATPases Associated with Various 265 713 forCellular Activities 7968 ATPases Associated with Various 152 616 revCellular Activities 8009 ATPases Associated with Various 12 510 forCellular Activities 8018 ATPases Associated with Various 125 658 forCellular Activities 8060 ATPases Associated with Various 97 752 forCellular Activities 8093 ATPases Associated with Various 185 664 forCellular Activities 8128 ATPases Associated with Various 69 485 forCellular Activities 8266 ATPases Associated with Various 73 550 forCellular Activities 8273 ATPases Associated with Various 340 928 forCellular Activities 8386 ATPases Associated with Various 872 1390 revCellular Activities 8439 ATPases Associated with Various 122 635 forCellular Activities 8454 ATPases Associated with Various 84 492 revCellular Activities 8486 ATPases Associated with Various 31 434 revCellular Activities 8510 ATPases Associated with Various 953 1358 revCellular Activities 8557 ATPases Associated with Various 192 690 revCellular Activities 8572 ATPases Associated with Various 51 593 forCellular Activities 8578 ATPases Associated with Various 135 615 revCellular Activities 8674 ATPases Associated with Various 0 673 forCellular Activities 7719 Basic region plus leucine zipper 81 277 fortranscription factors 7811 C2 domain (prot. kinase C like) 403 582 for8522 C2 domain (prot. kinase C like) 493 637 for 8334 Cysteine proteases359 984 rev 7726 DEAD and DEAH box helicases 34 690 rev 7961 DEAD andDEAH box helicases 43 753 for 8613 DEAD and DEAH box helicases 426 719for 7810 Dual specificity phosphatase, catalytic 365 696 rev domain 7824Dual specificity phosphatase, catalytic 243 597 for domain 8183 Dualspecificity phosphatase, catalytic 786 1566 for domain 7691 EF-hand 556630 for 7767 Eukaryotic aspartyl proteases 116 763 for 7874 Eukaryoticaspartyl proteases 92 1008 rev 7999 Eukaryotic aspartyl proteases 73 603rev 8041 Eukaryotic aspartyl proteases 147 694 rev 8059 Eukaryoticaspartyl proteases 38 740 rev 8087 Eukaryotic aspartyl proteases 4041113 rev 8226 Eukaryotic aspartyl proteases 237 829 rev 8234 Eukaryoticaspartyl proteases 117 729 rev 8289 Eukaryotic aspartyl proteases 2171397 rev 8386 Eukaryotic aspartyl proteases 413 1366 rev 8387 Eukaryoticaspartyl proteases 8 710 rev 8444 Eukaryotic aspartyl proteases 291 1146rev 8526 Eukaryotic aspartyl proteases 216 1158 rev 8592 Eukaryoticaspartyl proteases 228 659 for 8619 Eukaryotic aspartyl proteases 2761291 rev 8685 Eukaryotic aspartyl proteases 525 1431 for 8064Fibronectin type II domain 455 565 rev 7875 G-protein alpha subunit 24583 rev 7717 Helicases conserved C-terminal domain 160 309 for 7748Helicases conserved C-terminal domain 363 560 rev 8288 Helix-loop-helixDNA binding domain 224 382 for 8277 kinase domain of tors 474 713 for7921 mkk like kinases 17 626 rev 7972 mkk like kinases 35 719 for 8135mkk like kinases 114 527 for 8622 mkk like kinases 9 463 for 7878Neurotransmitter-gated ion-channel 267 1411 for 8018Neurotransmitter-gated ion-channel 367 1168 for 8164Neurotransmitter-gated ion-channel 222 1024 for 8198Neurotransmitter-gated ion-channel 352 1273 for 8250Neurotransmitter-gated ion-channel 377 1159 for 8634Neurotransmitter-gated ion-channel 112 1120 for 7717 protein kinase 153743 for 7726 protein kinase 123 904 for 7801 protein kinase 471 1072 for7802 protein kinase 190 609 for 7806 protein kinase 235 641 for 7840protein kinase 8 711 rev 7863 protein kinase 90 537 for 7872 proteinkinase 200 524 rev 7878 protein kinase 706 1331 for 7918 protein kinase24 666 for 7921 protein kinase 56 593 rev 7940 protein kinase 263 824for 7946 protein kinase 217 779 for 7972 protein kinase 290 711 for 8073protein kinase 38 776 for 8147 protein kinase 14 657 for 8208 proteinkinase 202 644 rev 8265 protein kinase 1 656 for 8301 protein kinase 57689 for 8338 protein kinase 33 646 for 8387 protein kinase 630 1148 rev8550 protein kinase 49 761 rev 8622 protein kinase 0 463 for 8654protein kinase 77 590 for 7815 Protein Tyrosine Phosphatase 82 482 rev7865 Protein Tyrosine Phosphatase 71 461 rev 8158 Protein TyrosinePhosphatase 270 704 for 8293 Protein Tyrosine Phosphatase 359 851 for8371 Protein Tyrosine Phosphatase 56 680 for 7946 RNA recognition motif.(aka RRM, RBD, 165 365 for or RNP domain) 8290 RNA recognition motif.(aka RRM, RBD, 37 174 for or RNP domain) 8537 SH2 Domain 201 362 for7714 Thioredoxins 253 554 for 7675 Trypsin 252 1007 rev 8386 Trypsin 3501164 rev 8437 Trypsin 447 1211 rev 8517 Trypsin 14 765 rev 8526 Trypsin700 1556 rev 8534 Trypsin 47 670 rev 8377 WD domain, G-beta repeats 70161 for 7675 wnt family of developmental signaling 282 1017 rev proteins7749 wnt family of developmental signaling 154 978 rev proteins 7874 wntfamily of developmental signaling 38 858 rev proteins 7922 wnt family ofdevelopmental signaling 574 1318 rev proteins 7971 wnt family ofdevelopmental signaling 578 1313 rev proteins 8000 wnt family ofdevelopmental signaling 205 1068 rev proteins 8088 wnt family ofdevelopmental signaling 2 824 rev proteins 8100 wnt family ofdevelopmental signaling 621 1420 rev proteins 8225 wnt family ofdevelopmental signaling 394 1343 rev proteins 8241 wnt family ofdevelopmental signaling 162 1027 rev proteins 8300 wnt family ofdevelopmental signaling 274 1405 rev proteins 8334 wnt family ofdevelopmental signaling 560 1195 rev proteins 8386 wnt family ofdevelopmental signaling 250 1273 rev proteins 8387 wnt family ofdevelopmental signaling 523 1409 rev proteins 8390 wnt family ofdevelopmental signaling 297 1237 rev proteins 8437 wnt family ofdevelopmental signaling 51 1002 rev proteins 8439 wnt family ofdevelopmental signaling 28 1180 rev proteins 8444 wnt family ofdevelopmental signaling 638 1614 rev proteins 8469 wnt family ofdevelopmental signaling 30 1078 rev proteins 8505 wnt family ofdevelopmental signaling 4 1074 rev proteins 8506 wnt family ofdevelopmental signaling 208 1107 rev proteins 8510 wnt family ofdevelopmental signaling 242 1068 rev proteins 8517 wnt family ofdevelopmental signaling 159 1057 rev proteins 8526 wnt family ofdevelopmental signaling 844 1691 rev proteins 8532 wnt family ofdevelopmental signaling 107 784 rev proteins 8534 wnt family ofdevelopmental signaling 127 1226 rev proteins 8559 wnt family ofdevelopmental signaling 5 704 rev proteins 8569 wnt family ofdevelopmental signaling 328 1193 rev proteins 8607 wnt family ofdevelopmental signaling 341 1222 rev proteins 8619 wnt family ofdevelopmental signaling 820 1617 rev proteins 8624 wnt family ofdevelopmental signaling 461 1283 rev proteins 7831 Zinc finger, C2H2type 495 557 for 8038 Zinc finger, C2H2 type 500 562 for 8114 Zincfinger, C2H2 type 279 341 for 8350 Zinc finger, C2H2 type 148 210 for8611 Zinc finger, C2H2 type 422 484 for

TABLE 42B Profile Hits for Contigs SEQ ID NO: Description Start Stop Dir8737 ATPases Associated with Various Cellular 118 661 for Activities8751 ATPases Associated with Various Cellular 135 536 for Activities8781 ATPases Associated with Various Cellular 142 574 for Activities8744 DEAD and DEAH box helicases 66 931 rev 8782 Helicases conservedC-terminal domain 51 242 for 8757 Neurotransmitter-gated ion-channel 169738 rev 8736 Protein phosphatase 2A regulatory subunit 275 1510 for PR558751 Protein phosphatase 2A regulatory subunit 55 1087 for PR55 8766Protein phosphatase 2A regulatory subunit 13 1183 for PR55 8780 Proteinphosphatase 2A regulatory subunit 511 1861 rev PR55 8775 ProteinTyrosine Phosphatase 292 768 for 8764 Thioredoxins 182 475 for

Some polynucleotides exhibited multiple profile hits where the querysequence contains overlapping profile regions, and/or where the sequencecontains two different functional domains. Each of the profile hits ofTable 42A are described in more detail below. The acronyms for theprofiles (provided in parentheses) are those used to identify theprofile in the Pfam and Prosite databases. The Pfam database can beaccessed through many URLS. The Prosite database can be accessed at theExpasy website. The public information available on the Pfam and Prositedatabases regarding the various profiles, including but not limited tothe activities, function, and consensus sequences of various proteinsfamilies and protein domains, is incorporated herein by reference.

14-3-3 Family (14_(—)3_(—)3). Some SEQ ID NOS corresponds to a sequenceencoding a 14-3-3 protein family member. The 14-3-3 protein familyincludes a group of closely related acidic homodimeric proteins of about30 kD first identified as very abundant in mammalian brain tissues andlocated preferentially in neurons (Aitken et al. Trends Biochem. Sci.(1995) 20:95-97; Morrison Science (1994) 266:56-57; and Xiao et al.Nature (1995) 376:188-191). The 14-3-3 proteins have multiple biologicalactivities, including a key role in signal transduction pathways and thecell cycle. 14-3-3 proteins interact with kinases (e.g., PKC or Raf-1),and can also function as protein-kinase dependent activators of tyrosineand tryptophan hydroxylases. The 14-3-3 protein sequences are extremelywell conserved, and include two highly conserved regions: the first is apeptide of 11 residues located in the N-terminal section; the second, a20 amino acid region located in the C-terminal section.

3′5′-Cyclin Nucleotide Phosphodiesterases (PDEase). Some SEQ ID NOSrepresent a polynucleotide encoding a novel 3′5′-cyclic nucleotidephosphodiesterase. PDEases catalyze the hydrolysis of cAMP or cGMP tothe corresponding nucleoside 5′ monophosphates (Charbonneau et al, Proc.Natl. Acad. Sci. U.S.A. (1986) 83:9308). There are at least sevendifferent subfamilies of PDEases (Beavo et al., Trends Pharmacol. Sci.(1990) 11:150; http://weber.u.washington.edu/˜pde/: 1) Type 1,calmodulin/calcium-dependent PDEases; 2) Type 2, cGMP-stimulatedPDEases; 3) Type 3, cGMP-inhibited PDEases; 4) Type 4, cAMP-specificPDEases; 5) Type 5, cGMP-specific PDEases; 6) Type 6,rhodopsin-sensitive cGMP-specific PDEases; and 7) Type 7, High affinitycAMP-specific PDEases. All PDEase forms share a conserved domain ofabout 270 residues.

Four Transmembrane Integral Membrane Proteins (transmembrane4). Some SEQID NOS correspond to a sequence encoding a member of the fourtransmembrane segments integral membrane protein family (tm4 family).The tm4 family of proteins includes a number of evolutionarily-relatedeukaryotic cell surface antigens (Levy et al., J. Biol. Chem., (1991)266:14597; Tomlinson et al., Eur. J. Immunol. (1993) 23:136; Barclay etal. The leucocyte antigen factbooks. (1993) Academic Press, London/SanDiego). The tm4 family members are type III membrane proteins, which areintegral membrane proteins containing an N-terminal membrane-anchoringdomain that functions both as a translocation signal and as a membraneanchor. The family members also contain three additional transmembraneregions, at least seven conserved cysteines residues, and are ofapproximately the same size (218 to 284 residues). The consensus patternspans a conserved region including two cysteines located in a shortcytoplasmic loop between two transmembrane domains:

Seven Transmembrane Integral Membrane Proteins—Rhodopsin Family(7tm_(—)1). Some SEQ ID NOS correspond to a sequence encoding a memberof the seven transmembrane (7tm) receptor rhodopsin family. G-proteincoupled receptors of the (7tm) rhodopsin family include hormones,neurotransmitters, and light receptors that transduce extracellularsignals by interaction with guanine nucleotide-binding (G) proteins(Strosberg Eur. J. Biochem. (1991) 196:1, Kerlavage Curr. Opin. Struct.Biol. (1991) 1:394, Probst, et al., DNA Cell Biol. (1992) 11:1,Savarese, et al., Biochem. J. (1992) 283:1)

Seven Transmembrane Integral Membrane Proteins—Secretin Family(7tm_(—)2). Some SEQ ID NOS correspond to a sequence encoding a memberof the seven transmembrane receptor (7tm) secretin family (Jueppner etal. Science (1991) 254:1024; Hamann et al. Genomics (1996) 32:144). TheN-terminal extracellular domain of these receptors contains fiveconserved cysteines residues involved in disulfide bonds, with aconsensus pattern in the region that spans the first three cysteines.One of the most highly conserved regions spans the C-terminal part ofthe last transmembrane region and the beginning of the adjacentintracellular region and is used as a second signature pattern.

ATPases Associated with Various Cellular Activities (ATPases). Severalof the polynucleotides of the invention correspond to a sequence thatencodes a member of a family of ATPases Associated with diverse cellularActivities (AAA). The AAA protein family is composed of a large numberof ATPases that share a conserved region of about 220 amino acidscontaining an ATP-binding site (Froehlich et al., J. Cell Biol. (1991)114:443; Erdmann et al. Cell (1991) 64:499; Peters et al., EMBO J.(1990) 9:1757; Kunau et al., Biochimie (1993) 75:209-224; Confalonieriet al., BioEssays (1995) 17:639). The AAA domain, which can be presentin one or two copies, acts as an ATP-dependent protein clamp(Confalonieri et al. (1995) BioEssays 17:639) and contains a highlyconserved region located in the central part of the domain.

Basic Region Plus Leucine Zipper Transcription Factors (BZIP). One SEQID NO represents a polynucleotide encoding a novel member of the familyof basic region plus leucine zipper transcription factors. The bZIPsuperfamily (Hurst, Protein Prof. (1995) 2:105; and Ellenberger, Curr.Opin. Struct. Biol. (1994) 4:12) of eukaryotic DNA-binding transcriptionfactors encompasses proteins that contain a basic region mediatingsequence-specific DNA-binding followed by a leucine zipper required fordimerization.

C2 domain (C2). Some SEQ ID NOS correspond to a sequence encoding a C2domain, which is involved in calcium-dependent phospholipid binding(Davletov J. Biol. Chem. (1993) 268:26386-26390) or, in proteins that donot bind calcium, the domain may facilitate binding toinositol-1,3,4,5-tetraphosphate (Fukuda et al. J. Biol. Chem. (1994)269:29206-29211; Sutton et al. Cell (1995) 80:929-938).

Cysteine proteases (Cys-protease). One SEQ ID NO represents apolynucleotide encoding a protein having a eukaryotic thiol (cysteine)protease active site. Cysteine proteases (Dufour Biochimie (1988)70:1335) are a family of proteolytic enzymes that contain an active sitecysteine. Catalysis proceeds through a thioester intermediate and isfacilitated by a nearby histidine side chain; an asparagine completesthe essential catalytic triad.

DEAD and DEAH box families ATP-dependent helicases (Dead_box_helic).Some SEQ ID NOS represent polynucleotides encoding a novel member of theDEAD and DEAH box families (Schmid et al., Mol. Microbiol. (1992) 6:283;Linder et al., Nature (1989) 337:121; Wassarman, et al., Nature (1991)349:463). All members of these families are involved in ATP-dependent,nucleic-acid unwinding. All DEAD box family members share a number ofconserved sequence motifs, some of which are specific to the DEADfamily, with others shared by other ATP-binding proteins or by proteinsbelonging to the helicases ‘superfamily’ (Hodgman Nature (1988) 333:22and Nature (1988) 333:578 (Errata);http://www.expasy.ch/www/linder/HELICASES_TEXT.html). One of thesemotifs, called the ‘D-E-A-D-box’, represents a special version of the Bmotif of ATP-binding proteins. Proteins that have His instead of thesecond Asp and are ‘D-E-A-H-box’ proteins (Wassarman et al., Nature(1991) 349:463; Harosh, et al., Nucleic Acids Res. (1991) 19:6331;Koonin, et al., J. Gen. Virol. (1992) 73:989;http://www.expasy.ch/www/linder/HELICASES_TEXT.html).

Dual specificity phosphatase (DSPc). Dual specificity phosphatases(DSPs) are Ser/Thr and Tyr protein phosphatases that comprise a tertiaryfold highly similar to that of tyrosine-specific phosphatases, exceptfor a “recognition” region connecting helix alpha1 to strand beta1. Thistertiary fold may determine differences in substrate specific betweenVH-1 related dual specificity phosphatase (VHR), the protein tyrosinephosphatases (PTPs), and other DSPs. Phosphatases are important in thecontrol of cell growth, proliferation, differentiation andtransformation.

EF Hand (EFhand). One SEQ ID NO corresponds to a polynucleotide encodinga member of the EF-hand protein family, a calcium binding domain sharedby many calcium-binding proteins belonging to the same evolutionaryfamily (Kawasaki et al., Protein. Prof. (1995) 2:305-490). The domain isa twelve residue loop flanked on both sides by a twelve residuealpha-helical domain, with a calcium ion coordinated in a pentagonalbipyramidal configuration. The six residues involved in the binding arein positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y,Z, −Y, −X and −Z. The invariant Glu or Asp at position 12 provides twooxygens for liganding Ca (bidentate ligand).

Eukaryotic Aspartyl Proteases (asp). Several of the polynucleotides ofthe invention correspond to a sequence encoding a novel eukaryoticaspartyl protease. Aspartyl proteases, known as acid proteases, (EC3.4.23.-) are a widely distributed family of proteolytic enzymes(Foltmann., Essays Biochem. (1981) 17:52; Davies, Annu. Rev. Biophys.Chem. (1990) 19:189; Rao, et al., Biochemistry (1991) 30:4663) known toexist in vertebrates, fungi, plants, retroviruses and some plantviruses. Aspartate proteases of eukaryotes are monomeric enzymes whichconsist of two domains. Each domain contains an active site centered ona catalytic aspartyl residue.

Fibronectin Type II collagen-binding domain (FntypeII). One SEQ ID NOcorresponds to a polynucleotide encoding a polypeptide having a type IIfibronectin collagen binding domain. Fibronectin is a plasma proteinthat binds cell surfaces and various compounds including collagen,fibrin, heparin, DNA, and actin. The major part of the sequence offibronectin consists of the repetition of three types of domains, calledtype I, II, and III (Skorstengaardet al., Eur. J. Biochem. (1986)161:441). The type II domain, which is duplicated in fibronectin, isapproximately forty residues long, contains four conserved cysteinesinvolved in disulfide bonds and is part of the collagen-binding regionof fibronectin.

G-Protein Alpha Subunit (G-alpha). One SEQ ID NO corresponds to a geneencoding a member of the G-protein alpha subunit family. G-proteins area family of membrane-associated proteins that coupleextracellularly-activated integral-membrane receptors to intracellulareffectors, such as ion channels and enzymes that vary the concentrationof second messenger molecules. G-proteins are composed of 3 subunits(alpha, beta and gamma) which, in the resting state, associate as atrimer at the inner face of the plasma membrane. The alpha subunit,which binds GTP and exhibits GTPase activity, is about 350-400 aminoacids in length with a molecular weight in the range of 40-45 kDa.Seventeen distinct types of alpha subunit have been identified inmammals, and fall into 4 main groups on the basis of both sequencesimilarity and function: alpha-s, alpha-q, alpha-i and alpha-12 (Simonet al., Science (1993) 252:802). They are often N-terminally acylated,usually with myristate and/or palmitoylate, and these fatty acidmodifications can be important for membrane association andhigh-affinity interactions with other proteins.

Helicases conserved C-terminal domain (helicase_C). Some SEQ ID NOSrepresent polynucleotides encoding novel members of the DEAD/H helicasefamily. The DEAD and DEAH families are described above.

Helix-Loop-Helix (HLH) DNA Binding Domain (HLH). One SEQ ID NOcorresponds to a sequence encoding an HLH domain. The HLH domain, whichnormally spans about 40 to 50 amino acids, is present in a number ofeukaryotic transcription factors. The HLH domain is formed of twoamphipathic helices joined by a variable length linker region that formsa loop that mediates protein dimerization (Murre et al. Cell (1989)56:777-783). Basic HLH proteins (bHLH), which have an extra basic regionof about 15 amino acid residues adjacent the HLH domain and specificallybind to DNA, include two groups: class A (ubiquitous) and class B(tissue-specific). bHLH family members bind variations of the E-boxmotif (CANNTG). The homo- or heterodimerization mediated by the HLHdomain is independent of, but necessary for DNA binding, as two basicregions are required for DNA binding activity. The HLH proteins lackingthe basic domain function as negative regulators since they formheterodimers, but fail to bind DNA.

Kinase Domain of Tors. The TOR profile is directed towards a lipidkinase protein family. This family is composed of large proteins with alipid and protein kinase domain and characterized through theirsensitivity to rapamycin (an antifungal compound). TOR proteins areinvolved in signal transduction downstream of PI3 kinase and many othersignals. TOR (also called FRAP, RAFT) plays a role in regulating proteinsynthesis and cell growth, and in yeast controls translation initiationand early G1 progression. See, e.g., Barbet et al. Mol Biol Cell. (1996)7(1):25-42; Helliwell et al. Genetics (1998) 148:99-112.

MAP kinase kinase (mkk). Some SEQ ID NOS represent members of the MAPkinase kinase (mkk) family. MAP kinases (MAPK) are involved in signaltransduction, and are important in cell cycle and cell growth controls.The MAP kinase kinases (MAPKK) are dual-specificity protein kinaseswhich phosphorylate and activate MAP kinases. MAPKK homologues have beenfound in yeast, invertebrates, amphibians, and mammals. Moreover, theMAPKK/MAPK phosphorylation switch constitutes a basic module activatedin distinct pathways in yeast and in vertebrates. MAPKKs are essentialtransducers through which signals must pass before reaching the nucleus.For review, see, e.g., Biologique Biol Cell (1993) 79:193-207; Nishidaet al., Trends Biochem Sci (1993) 18:128-31; Ruderman Curr Opin CellBiol (1993) 5:207-13; Dhanasekaran et al., Oncogene (1998) 17:1447-55;Kiefer et al., Biochem Soc Trans (1997) 25:491-8; and Hill, Cell Signal(1996) 8:533-44.

Neurotransmitter-Gated Ion-Channel (neur_chan). Several of the sequencescorrespond to a sequence encoding a neurotransmitter-gated ion channel.Neurotransmitter-gated ion-channels, which provide the molecular basisfor rapid signal transmission at chemical synapses, are post-synapticoligomeric transmembrane complexes that transiently form a ionic channelupon the binding of a specific neurotransmitter. Five types ofneurotransmitter-gated receptors are known: 1) nicotinic acetylcholinereceptor (AchR); 2) glycine receptor; 3) gamma-aminobutyric-acid (GABA)receptor; 4) serotonin 5HT3 receptor; and 5) glutamate receptor. Allknown sequences of subunits from neurotransmitter-gated ion-channels arestructurally related, and are composed of a large extracellularglycosylated N-terminal ligand-binding domain, followed by threehydrophobic transmembrane regions that form the ionic channel, followedby an intracellular region of variable length. A fourth hydrophobicregion is found at the C-terminal of the sequence.

Protein Kinase (protkinase). Several sequences represent polynucleotidesencoding protein kinases, which catalyze phosphorylation of proteins ina variety of pathways, and are implicated in cancer. Eukaryotic proteinkinases (Hanks, et al., FASEB J. (1995) 9:576; Hunter, Meth. Enzymol.(1991) 200:3; Hanks, et al., Meth. Enzymol. (1991) 200:38; Hanks, Curr.Opin. Struct. Biol. (1991) 1:369; Hanks et al., Science (1988) 241:42)belong to a very extensive family of proteins that share a conservedcatalytic core common to both serine/threonine and tyrosine proteinkinases. There are a number of conserved regions in the catalytic domainof protein kinases. The first region, located in the N-terminalextremity of the catalytic domain, is a glycine-rich stretch of residuesin the vicinity of a lysine residue, which has been shown to be involvedin ATP binding. The second region, located in the central part of thecatalytic domain, contains a conserved an aspartic acid residue that isimportant for the catalytic activity of the enzyme (Knighton, et al.,Science (1991) 253:407).

The protein kinase profile includes two signature patterns for thissecond region: one specific for serine/threonine kinases and the otherfor tyrosine kinases. A third profile is based on the alignment in(Hanks, et al., FASEB J. (1995) 9:576) and covers the entire catalyticdomain.

Protein Tyrosine Phosphatase (Y_phosphatase) (PTPase). Some SEQ ID NOSrepresent polynucleotides encoding a tyrosine-specific proteinphosphatase, a kinase that catalyzes the removal of a phosphate groupsattached to a tyrosine residue (EC 3.1.3.48) (PTPase) (Fischer et al.,Science (1991) 253:401; Charbonneau et al., Annu. Rev. Cell Biol. (1992)8:463; Trowbridge Biol. Chem. (1991) 266:23517; Tonks et al., TrendsBiochem. Sci. (1989) 14:497; and Hunter, Cell (1989) 58:1013). PTPasesare important in the control of cell growth, proliferation,differentiation and transformation. Multiple forms of PTPase have beencharacterized and can be classified into two categories: soluble PTPasesand transmembrane receptor proteins that contain PTPase domain(s).Structurally, all known receptor PTPases are made up of a variablelength extracellular domain, followed by a transmembrane region and aC-terminal catalytic cytoplasmic domain. PTPase domains consist of about300 amino acids. Two conserved cysteines are absolutely required foractivity, with a number of other conserved residues in the immediatevicinity also important for activity.

RNA Recognition Motif (rrm). Some SEQ ID NOS correspond to sequenceencoding an RNA recognition motif, also known as an RRM, RBD, or RNPdomain. This domain, which is about 90 amino acids long, is contained ineukaryotic proteins that bind single-stranded RNA (Bandziulis et al.Genes Dev. (1989) 3:431-437; Dreyfuss et al. Trends Biochem. Sci. (1988)13:86-91). Two regions within the RNA-binding domain are highlyconserved: the first is a hydrophobic segment of six residues (which iscalled the RNP-2 motif), the second is an octapeptide motif (which iscalled RNP-1 or RNP-CS).

SH2 Domain (SH2). One SEQ ID NO corresponds to a sequence encoding anSH2 domain. The Src homology 2 (SH2) domain includes an approximately100 amino acid residue domain, which is conserved in the oncoproteinsSrc and Fps, as well as in many other intracellular signal-transducingproteins (Sadowski et al. Mol. Cell. Biol. (1986) 6:4396-4408; Russel etal. FEBS Lett. (1992) 304:15-20). SH2 domains function as regulatorymodules of intracellular signaling cascades by interacting with highaffinity to phosphotyrosine-containing target peptides in asequence-specific and strictly phosphorylation-dependent manner. The SH2domain has a conserved 3D structure consisting of two alpha helices andsix to seven beta-strands. The core of the domain is formed by acontinuous beta-meander composed of two connected beta-sheets (Kuriyanet al. Curr. Opin. Struct. Biol. (1993) 3:828-837).

Thioredoxin family active site (Thioredox). One SEQ ID NO represents apolynucleotide encoding a protein of the thioredoxin family.Thioredoxins are small proteins of approximately one hundred amino acidresidues that participate in various redox reactions via the reversibleoxidation of an active center disulfide bond (Holmgren, Annu. Rev.Biochem. (1985) 54:237; Gleason, et al., FEMS Microbiol. Rev. (1988)54:271; Holmgren A. J. Biol. Chem. (1989) 264:13963; Eklund, et al.Proteins (1991) 11:13). Thioredoxins exist in either reduced or oxidizedforms where the two cysteine residues are linked in an intramoleculardisulfide bond. The sequence around the redox-active disulfide bond iswell conserved.

Trypsin (trypsin). Some SEQ ID NOS correspond to novel serine proteasesof the trypsin family. The catalytic activity of the serine proteasesfrom the trypsin family is provided by a charge relay system involvingan aspartic acid residue hydrogen-bonded to a histidine, which itself ishydrogen-bonded to a serine. The sequences in the vicinity of the activesite serine and histidine residues are well conserved (Brenner Nature(1988) 334:528). All sequences known to belong to this family aredetected by the above consensus sequences, except for 18 differentproteases which have lost the first conserved glycine. If a proteinincludes both the serine and the histidine active site signatures, theprobability of it being a trypsin family serine protease is 100%.

WD Domain G-Beta Repeats (WD_domain). One SEQ ID NO represents a memberof the WD domain/G-beta repeat family. Beta-transducin (G-beta) is oneof the three subunits (alpha, beta, and gamma) of the guaninenucleotide-binding proteins (G proteins) which act as intermediaries inthe transduction of signals generated by transmembrane receptors(Gilman, Annu. Rev. Biochem. (1987) 56:615). The alpha subunit binds toand hydrolyzes GTP; the beta and gamma subunits are required for thereplacement of GDP by GTP as well as for membrane anchoring and receptorrecognition. In higher eukaryotes, G-beta exists as a small multigenefamily of highly conserved proteins of about 340 amino acid residues.Structurally, G-beta has eight tandem repeats of about 40 residues, eachcontaining a central Trp-Asp motif (this type of repeat is sometimescalled a WD-40 repeat).

wnt Family of Developmental Signaling Proteins (Wnt_dev_sign). Severalof the sequences correspond to novel members of the wnt family ofdevelopmental signaling proteins. Wnt-1 (previously known as int-I), theseminal member of this family, (Nusse, Trends Genet. (1988) 4:291) playsa role in intercellular communication and is important in centralnervous system development. All wnt family proteins share the followingfeatures characteristic of secretory proteins: a signal peptide, severalpotential N-glycosylation sites and 22 conserved cysteines that may beinvolved in disulfide bonds. Wnt proteins generally adhere to the plasmamembrane of secreting cells and are therefore likely to signal over onlyfew cell diameters.

Zinc Fin ger, C2H2 Type (Zincfing_C2H2). Some SEQ ID NOS correspond topolynucleotides encoding members of the C2H2 type zinc finger proteinfamily, which contain zinc finger domains that facilitate nucleic acidbinding (Klug et al., Trends Biochem. Sci. (1987) 12:464; Evans et al.,Cell (1988) 52:1; Payre et al., FEBS Lett. (1988) 234:245; Miller etal., EMBO J. (1985) 4:1609; and Berg, Proc. Natl. Acad. Sci. USA (1988)85:99). In addition to the conserved zinc ligand residues, a number ofother positions are also important for the structural integrity of theC2H2 zinc fingers. (Rosenfeld et al., J. Biomol. Struct. Dyn. (1993)11:557) The best conserved position, which is generally an aromatic oraliphatic residue, is located four residues after the second cysteine.

Example 30 Differential Expression of Polynucleotides of the Invention:Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the inventionwas assessed in several libraries prepared from various sources,including cell lines and patient tissue samples. Table 43 provides asummary of these libraries, including the shortened library name (usedhereafter), the mRNA source used to prepared the cDNA library, the“nickname” of the library that is used in the tables below (in quotes),and the approximate number of clones in the library. TABLE 43Description of cDNA Libraries Number of Library Clones in (lib #)Description Cluster 1 Km12 L4 307133 Human Colon Cell Line, HighMetastatic Potential (derived from Km12C); “High Met Colon” 2 Km12C284755 Human Colon Cell Line, Low Metastatic Potential; “Low Met Colon”3 MDA-MB-231 326937 Human Breast Cancer Cell Line, High MetastaticPotential; micro- metastases in lung; “High Met Breast” 4 MCF7 318979Human Breast Cancer Cell, Non Metastatic; “Low Met Breast” 8 MV-522223620 Human Lung Cancer Cell Line, High Metastatic Potential; “High MetLung” 9 UCP-3 312503 Human Lung Cancer Cell Line, Low MetastaticPotential; “Low Met Lung” 12 Human microvascular endothelial cells(HMEC) - Untreated 41938 PCR (OligodT) cDNA library; “HMEC” 13 Humanmicrovascular endothelial cells (HMEC) - Basic fibroblast 42100 growthfactor (bFGF) treated PCR (OligodT) cDNA library; “HMEC-bFGF” 14 Humanmicrovascular endothelial cells (HMEC) - Vascular 42825 endothelialgrowth factor (VEGF) treated PCR (OligodT) cDNA library; “HMEC-VEGF” 15Normal Colon - UC#2 Patient 282722 PCR (OligodT) cDNA library; “NormalColon Tissue” 16 Colon Tumor - UC#2 Patient 298831 PCR (OligodT) cDNAlibrary; “Normal Colon Tumor Tissue” 17 Liver Metastasis from ColonTumor of UC#2 Patient 303467 PCR (OligodT) cDNA library; “High Met ColonTissue” 18 Normal Colon - UC#3 Patient 36216 PCR (OligodT) cDNA library;“Normal Colon Tissue” 19 Colon Tumor - UC#3 Patient 41388 PCR (OligodT)cDNA library; “Colon Tumor Tissue” 20 Liver Metastasis from Colon Tumorof UC#3 Patient 30956 PCR (OligodT) cDNA library; “High Met ColonTissue” 21 GRRpz 164801 Human Prostate Cell Line; “Normal Prostate” 22Woca 162088 Human Prostate Cancer Cell Line; “Prostate Cancer”

The KM12L4, KM12C, and MDA-MB-231 cell lines are described above. TheMCF7 cell line was derived from a pleural effusion of a breastadenocarcinoma and is non-metastatic. The MV-522 cell line is derivedfrom a human lung carcinoma and is of high metastatic potential. TheUCP-3 cell line is a low metastatic human lung carcinoma cell line; theMV-522 is a high metastatic variant of UCP-3. These cell lines arewell-recognized in the art as models for the study of human breast andlung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870(MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965(MDA-MB-231 and MCF-7); Ranson etal., Br J Cancer (1998) 77:1586(MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116(MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3);Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki etal., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., AnticancerRes (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997)8:696 (MV522)). The samples of libraries 15-20 are derived from twodifferent patients (UC#2, and UC#3). The bFGF-treated HMEC were preparedby incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMECwere prepared by incubation with 20 ng/ml VEGF for 2 hrs. Followingincubation with the respective growth factor, the cells were washed andlysis buffer added for RNA preparation. The GRRpz and WOca cell lineswere provided by Dr. Donna M. Peehl, Department of Medicine, StanfordUniversity School of Medicine. GRRpz was derived from normal prostateepithelium. The WOca cell line is a Gleason Grade 4 cell line.

Each of the libraries is composed of a collection of cDNA clones that inturn are representative of the mRNAs expressed in the indicated mRNAsource. In order to facilitate the analysis of the millions of sequencesin each library, the sequences were assigned to clusters. The concept of“cluster of clones” is derived from a sorting/grouping of cDNA clonesbased on their hybridization pattern to a panel of roughly 300 7 bpoligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29).Random cDNA clones from a tissue library are hybridized at moderatestringency to 300 7 bp oligonucleotides. Each oligonucleotide has somemeasure of specific hybridization to that specific clone. Thecombination of 300 of these measures of hybridization for 300 probesequals the “hybridization signature” for a specific clone. Clones withsimilar sequence will have similar hybridization signatures. Bydeveloping a sorting/grouping algorithm to analyze these signatures,groups of clones in a library can be identified and brought togethercomputationally. These groups of clones are termed “clusters”. Dependingon the stringency of the selection in the algorithm (similar to thestringency of hybridization in a classic library cDNA screeningprotocol), the “purity” of each cluster can be controlled. For example,artifacts of clustering may occur in computational clustering just asartifacts can occur in “wet-lab” screening of a cDNA library with 400 bpcDNA fragments, at even the highest stringency. The stringency used inthe implementation of cluster herein provides groups of clones that arein general from the same cDNA or closely related cDNAs. Closely relatedclones can be a result of different length clones of the same cDNA,closely related clones from highly related gene families, or splicevariants of the same cDNA.

Differential expression for a selected cluster was assessed by firstdetermining the number of cDNA clones corresponding to the selectedcluster in the first library (Clones in 1^(st)), and the determining thenumber of cDNA clones corresponding to the selected cluster in thesecond library (Clones in 2^(nd)). Differential expression of theselected cluster in the first library relative to the second library isexpressed as a “ratio” of percent expression between the two libraries.In general, the “ratio” is calculated by: 1) calculating the percentexpression of the selected cluster in the first library by dividing thenumber of clones corresponding to a selected cluster in the firstlibrary by the total number of clones analyzed from the first library;2) calculating the percent expression of the selected cluster in thesecond library by dividing the number of clones corresponding to aselected cluster in a second library by the total number of clonesanalyzed from the second library; 3) dividing the calculated percentexpression from the first library by the calculated percent expressionfrom the second library. If the “number of clones” corresponding to aselected cluster in a library is zero, the value is set at 1 to aid incalculation. The formula used in calculating the ratio takes intoaccount the “depth” of each of the libraries being compared, i.e., thetotal number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentiallyexpressed between two samples when the ratio value is greater than atleast about 2, preferably greater than at least about 3, more preferablygreater than at least about 5, where the ratio value is calculated usingthe method described above. The significance of differential expressionis determined using a z score test (Zar, Biostatistical Analysis,Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298(1974).

Examples 31-38 Differential Expression of Polynucleotides of theInvention

A number of polynucleotide sequences have been identified that aredifferentially expressed between, for example, cells derived from highmetastatic potential cancer tissue and low metastatic cancer cells, andbetween cells derived from high metastatic potential cancer tissue andnormal tissue. Evaluation of the levels of expression of the genescorresponding to these sequences can be valuable in diagnosis,prognosis, and/or treatment (e.g., to facilitate rationale design oftherapy, monitoring during and after therapy, etc.). Moreover, the genescorresponding to differentially expressed sequences described herein canbe therapeutic targets due to their involvement in regulation (e.g.,inhibition or promotion) of development of, for example, the metastaticphenotype. For example, sequences that correspond to genes that areincreased in expression in high metastatic potential cells relative tonormal or non-metastatic tumor cells may encode genes or regulatorysequences involved in processes such as angiogenesis, differentiation,cell replication, and metastasis.

Detection of the relative expression levels of differentially expressedpolynucleotides described herein can provide valuable information toguide the clinician in the choice of therapy. For example, a patientsample exhibiting an expression level of one or more of thesepolynucleotides that corresponds to a gene that is increased inexpression in metastatic or high metastatic potential cells may warrantmore aggressive treatment for the patient. In contrast, detection ofexpression levels of a polynucleotide sequence that corresponds toexpression levels associated with that of low metastatic potential cellsmay warrant a more positive prognosis than the gross pathology wouldsuggest.

A number of polynucleotide sequences of the present invention aredifferentially expressed between human microvascular endothelial cells(HMEC) that have been treated with growth factors relative to untreatedHMEC. Sequences that are differentially expressed between growthfactor-treated FMEC and untreated HMEC can represent sequences encodinggene products involved in angiogenesis, metastasis (cell migration), andother development and oncogenic processes. For example, sequences thatare more highly expressed in HMEC treated with growth factors (such asbFGF or VEGF) relative to untreated HMEC can serve as markers of cancercells of higher metastatic potential. Detection of expression of thesesequences in colon cancer tissue can be valuable in determiningdiagnostic, prognostic and/or treatment information associated with theprevention of achieving the malignant state in these tissues, and can beimportant in risk assessment for a patient. A patient sample displayingan increased level of one or more of these polynucleotides may thuswarrant closer attention or more frequent screening procedures to catchthe malignant state as early as possible.

The differential expression of the polynucleotides described herein canthus be used as, for example, diagnostic markers, prognostic markers,for risk assessment, patient treatment and the like. Thesepolynucleotide sequences can also be used in combination with otherknown molecular and/or biochemical markers. The following examplesprovide relative expression levels of polynucleotides from specifiedcell lines and patient tissue samples.

Example 31 High Metastatic Potential Breast Cancer Versus Low MetastaticBreast Cancer Cells

The following tables summarize polynucleotides that represent genes thatare differentially expressed between high metastatic potential and lowmetastatic potential breast cancer cells. TABLE 44 High metastaticpotential breast (lib3) > low metastatic potential (lib4) breast cancercells SEQ ID NO: Lib3 Clones Lib4 Clones Lib3/Lib4 7309 40 0 39 7634 603 20 7562 14 0 14 7452 10 0 10 7479 10 1 10 7254 10 1 10 6537 10 1 107434 10 0 10 7522 19 2 9 7643 9 1 9 7409 8 1 8 6937 8 1 8 7630 8 0 87599 8 0 8 6925 8 1 8 7504 8 0 8 7543 7 0 7 7485 7 0 7 6452 7 0 7 7588 70 7 7639 22 3 7 6895 7 0 7 7533 6 0 6 7347 6 0 6 7068 18 3 6 7578 6 0 67395 6 0 6 6205 24 4 6 7654 6 0 6 7451 6 0 6 7644 11 2 5 6346 10 2 57015 26 6 4 6454 36 12 3 7621 75 28 3 7253 49 17 3

TABLE 45 Low metastatic potential breast (lib4) > high metastaticpotential breast cancer cells (lib3) SEQ ID NO: Lib3 Clones Lib4 ClonesLib4/Lib3 6344 0 58 59 6822 1 23 24 6110 1 19 19 6795 0 14 14 6859 1 1414 6116 1 13 13 6175 1 13 13 6811 0 10 10 7087 0 8 8 7295 0 8 8 6803 0 77 7224 4 26 7 6987 0 6 6 7242 2 11 6 6827 7 44 6 7614 3 15 5 6436 3 13 47045 4 13 3 7343 7 18 3 7281 497 1216 3

Example 32 High Metastatic Potential Lung Cancer Versus Low MetastaticLung Cancer Cells

The following summarizes polynucleotides that represent genesdifferentially expressed between high metastatic potential lung cancercells and low metastatic potential lung cancer cells: TABLE 46 Highmetastatic potential lung (lib8) > low metastatic potential lung (lib9)lung cancer cells SEQ ID Lib8 NO: Clones Lib9 Clones Lib8/Lib9 6246 31 043 6747 43 2 30 7394 14 1 20 6153 11 0 15 6721 7 0 10 7418 7 1 10 6132 70 10 6717 18 3 8 6311 6 1 8 6657 19 4 7 6343 5 0 7 6295 5 0 7 7094 5 0 76598 5 0 7 7478 8 2 6 7277 17 4 6 7405 8 2 6 7253 15 4 5 7356 14 5 47281 710 266 4 7621 21 10 3

TABLE 47 Low metastatic potential lung (lib9) > high metastaticpotential lung (lib8) cancer cells SEQ ID Lib8 NO: Clones Lib9 ClonesLib9/Lib8 7020 1 13 9 6918 1 13 9 6824 1 12 9 6437 1 12 9 7623 3 31 76794 4 26 5 7045 2 15 5 6840 3 23 5 7069 8 27 2

Example 33 High Metastatic Potential Colon Cancer Versus Low MetastaticColon Cancer Cells

Tables 48 and 49 summarize polynucleotides that represent genesdifferentially expressed between high metastatic potential and lowmetastatic potential colon cancer cells: TABLE 48 High metastaticpotential (lib1) > low metastatic potential (lib2) colon cancer cellsSEQ ID Lib1 Lib2 NO: Clones Clones Lib1/Lib2 6344 67 2 31 6183 12 0 116794 11 0 10 6153 13 3 4 7020 24 10 2 7345 24 9 2

TABLE 49 Low metastatic potential (lib2) > high metastatic potentialcolon cancer (lib1) cells SEQ ID Lib2 NO: Lib1 Clones Clones Lib2/Lib17364 1 17 18 7210 0 15 16 7128 1 14 15 6205 5 60 13 7069 1 11 12 6187 111 12 7078 0 9 10 7363 3 28 10 6189 1 8 9 7652 1 8 9 7347 0 8 9 7302 217 9 6908 0 8 9 7350 0 7 8 7316 0 7 8 6862 0 7 8 7252 0 7 8 7103 0 7 87077 0 7 8 6858 0 7 8 6972 0 6 6 7330 2 11 6 7279 0 6 6 7140 2 12 6 68810 6 6 7165 3 17 6 6866 0 6 6 6874 0 6 6 6888 0 6 6 6918 2 10 5 7354 7 234 7320 7 17 3 7080 8 19 3 6937 10 28 3 6435 14 34 3 7309 11 29 3 7297 514 3 7288 22 48 2

Example 34 High Metastatic Potential Colon Cancer Patient Tissue Vs.Normal Patient Tissue

Table 50 summarizes polynucleotides that represent genes differentiallyexpressed between high metastatic potential colon cancer cells andnormal colon cells of patient tissue. TABLE 50 High metastatic potentialcolon tissue (lib17) vs. normal colon tissue (lib15) SEQ ID Lib15 Lib17NO: Clones Clones Lib17/Lib15 7518 1 13 12  7228 1 10 9 6826 1 9 8 74070 7 7 6174 9 48 5 6918 5 20 4 SEQ ID Lib15 Lib17 NO: Clones ClonesLib15/Lib17 6559 8 1 9

Example 35 High Tumor Potential Colon Tissue Vs. Metastasized ColonCancer Tissue

The following table summarizes polynucleotides that represent genesdifferentially expressed between high tumor potential colon cancer cellsand cells derived from high metastatic potential colon cells of apatient. TABLE 51 High tumor potential colon tissue (lib16) vs. highmetastatic colon tissue (lib17) SEQ ID Lib16 Lib17 NO: Clones ClonesLib16/Lib17 7281 14  4  4 SEQ ID Lib16 Lib17 NO: Clones ClonesLib17/Lib16 6918  2 20 10

Example 36 High Tumor Potential Colon Cancer Patient Tissue VersusNormal Patient

Tables 13 and 14 summarize polynucleotides that represent genesdifferentially expressed between high metastatic potential colon cancercells and normal colon cells in patient tissue: TABLE 52 Higherexpression in tumor potential colon tissue (lib16) vs. normal colontissue (lib15) SEQ ID Lib15 Lib16 NO: Clones Clones Lib16/Lib15 7407 0 88 6174 9 28 3

TABLE 53 Higher expression in normal colon tissue (lib15) vs. tumorpotential colon tissue (lib16) SEQ ID Lib16 NO: Lib15 Clones ClonesLib15/Lib16 6559 8 0 8 7195 12 3 4

Example 37 Growth Factor-Stimulated Human Microvascular EndothelialCells (HMEC) Relative to Untreated HMEC

The following tables summarize polynucleotides that represent genesdifferentially expressed between growth factor-treated and untreatedHMEC. TABLE 54 Higher expression in bFGF treated HMEC (lib13) vs.untreated HMEC (lib12) SEQ ID Lib12 NO: Clones Lib13 Clones Lib13/Lib127616 9 23 3 7634 17 35 2

TABLE 55 Higher expression in VEGF treated HMEC (lib14) vs. untreatedHMEC (lib12) SEQ ID Lib12 NO: Clones Lib14 Clones Lib14/Lib12 7250 2 126 7322 2 10 5 7634 17 38 2

Example 38 Polynucleotides Differentially Expressed in Human ProstateCancer Cells Relative to Normal Human Prostate Cells

The following tables summarize identified polynucleotides that representgenes differentially expressed between prostate cancer cells and normalprostate cells: TABLE 56 Higher expression in normal prostate cells(lib21) relative to prostate cancer cells (lib22) SEQ ID Lib21 NO:Clones Lib22 Clones Lib21/Lib22 7621 6 0 6 6344 116 51 2 7299 22 9 2

TABLE 57 Higher expression in prostate cancer cells (lib22) relative tonormal prostate cells (lib21) SEQ ID Lib21 Lib22 NO: Clones ClonesLib22/Lib21 7309 0 34 35 6436 1 12 12 6795 0 11 11

Example 39 Differential Expression Across Multiple Libraries

A number of polynucleotide sequences have been identified that representgenes that are differentially expressed across multiple libraries.Expression of these sequences in a tissue or any origin can be valuablein determining diagnostic, prognostic and/or treatment informationassociated with the prevention of achieving the malignant state in thesetissues, and can be important in risk assessment for a patient. Thesepolynucleotides can also serve as non-tissue specific markers of, forexample, risk of metastasis of a tumor. Table 58 summarizes this data.TABLE 58 Genes Differentially Expressed Across Multiple LibraryComparisons SEQ ID NO: Cell or Tissue Sample and Cancer State ComparedRatio 6153 High Met Lung (lib8) > Low Met Lung (lib9) 15 6153 High MetColon (lib1) > Low Met Colon (lib2) 4 6174 High Met Colon Tissue(lib17) > Normal Colon Tissue 5 (lib15) 6174 Normal Colon Tumor Tissue(lib16) > Normal Colon 3 Tissue (lib15) 6205 High Met Breast (lib3) >Low Met Breast (lib4) 6 6205 Low Met Colon (lib2) > High Met Colon(lib1) 13 6344 High Met Colon (lib1) > Low Met Colon (lib2) 31 6344Normal Prostate (lib21) > Prostate Cancer (lib22) 2 6344 Low Met Breast(lib4) > High Met Breast (lib3) 59 6436 Prostate Cancer (lib22) > NormalProstate (lib21) 12 6436 Low Met Breast (lib4)> High Met Breast (lib3) 46559 Normal Colon Tissue (lib15) > High Met Colon 9 Tissue (lib17) 6559Normal Colon Tissue (lib15) > Normal Colon 8 Tumor Tissue (lib16) 6794High Met Colon (lib1) > Low Met Colon (lib2) 10 6794 Low Met Lung(lib9) > High Met Lung (lib8) 5 6795 Low Met Breast (lib4) > High MetBreast (lib3) 14 6795 Prostate Cancer (lib22) > Normal Prostate (lib21)11 6918 High Met Colon Tissue (lib17) > Normal Colon 10 Tumor Tissue(lib16) 6918 Low Met Lung (lib9) > High Met Lung (lib8) 9 6918 Low MetColon (lib2) > High Met Colon (lib1) 5 6918 High Met Colon Tissue(lib17) > Normal 4 Colon Tissue (lib15) 6937 High Met Breast (lib3) >Low Met Breast (lib4) 8 6937 Low Met Colon (lib2) > High Met Colon(lib1) 3 7020 High Met Colon (lib1) > Low Met Colon (lib2) 2 7020 LowMet Lung (lib9) > High Met Lung (lib8) 9 7045 Low Met Lung (lib9) > HighMet Lung (lib8) 5 7045 Low Met Breast (lib4) > High Met Breast (lib3) 37069 Low Met Colon (lib2) > High Met Colon (lib1) 12 7069 Low Met Lung(lib9) > High Met Lung (lib8) 2 7253 High Met Lung (lib8) > Low Met Lung(lib9) 5 7253 High Met Breast (lib3) > Low Met Breast (lib4) 3 7281Normal Colon Tumor Tissue (lib16) > High Met 4 Colon Tissue (lib17) 7281High Met Lung (lib8) > Low Met Lung (lib9) 4 7281 Low Met Breast(lib4) > High Met Breast (lib3) 3 7309 High Met Breast (lib3) > Low MetBreast (lib4) 39 7309 Prostate Cancer (lib22) > Normal Prostate (lib21)35 7309 Low Met Colon (lib2) > High Met Colon (lib1) 3 7347 High MetBreast (lib3) > Low Met Breast (lib4) 6 7347 Low Met Colon (lib2) > HighMet Colon (lib1) 9 7407 Normal Colon Tumor Tissue (lib16) > Normal 8Colon Tissue (lib15) 7407 High Met Colon Tissue (lib17) > Normal 7 ColonTissue (lib15) 7621 Normal Prostate (lib21) > Prostate Cancer (lib22) 67621 High Met Lung (lib8) > Low Met Lung (lib9) 3 7621 High Met Breast(lib3) > Low Met Breast (lib4) 3 7634 High Met Breast (lib3) > Low MetBreast (lib4) 20 7634 HMEC-VEGF (lib14) > HMEC (lib12) 2 7634 HMEC-bFGF(lib13) > HMEC (lib12) 2Key for Table 58:High Met = high metastatic potential;Low Met = low metastatic potential;met = metastasized;tumor = non-metastasized tumor;HMEC = human microvascular endothelial cell;bFGF = bFGF treated;VEGF = VEGF treated.

Example 40 Identification of Contiguous Sequences Having aPolynucleotide of the Invention

The novel polynucleotides were used to screen publicly available andproprietary databases to determine if any of the polynucleotides of SEQID NOS:8707-8803 would facilitate identification of a contiguoussequence, e.g. the polynucleotides would provide sequence that wouldresult in 5′ extension of another DNA sequence, resulting in productionof a longer contiguous sequence composed of the provided polynucleotideand the other DNA sequence(s). Contiging was performed using theGelmerge application (default settings) of GCG from the Univ. ofWisconsin.

Using these parameters, 97 contiged sequences were generated. Thesecontiged sequences are provided as SEQ ID NOS: 8707-8803 (see Table41C). Table 41C provides the SEQ ID NO of the contig sequence, the nameof the sequence used to create the contig, and the accession number ofthe publicly available tentative human consensus (THC) sequence usedwith the sequence of the corresponding sequence name to provide thecontig. The sequence name of Table 41C can be correlated with the SEQ IDNO: of the polynucleotide of the invention using Tables 41A and 41B.TABLE 41C SEQ ID THC Accession NO: Sequence Name No. 8707RTA00000587F.p.24.1.Seq THC226834 8708 RTA00000629F.1.02.1.Seq THC2103248709 RTA00000623F.n.17.1.Seq THC208388 8710 RTA00000593F.i.08.2.SeqH91190 8711 RTA00000622F.b.03.1.Seq AA554045 8712RTA00000618F.e.06.1.Seq THC226692 8713 RTA00000592F.o.02.1.Seq AA0997898714 RTA00000618F.c.04.1.Seq THC222808 8715 RTA00000590F.i.01.1.SeqTHC173163 8716 RTA00000606F.o.14.1.Seq THC223717 8717RTA00000626F.d.07.1.Seq THC234888 8718 RTA00000587F.1.08.1.Seq THC1043848719 RTA00000586F.a.13.1.Seq THC140691 8720 RTA00000617F.a.17.1.SeqTHC221850 8721 RTA00000615F.b.23.1.Seq THC205191 8722RTA00000632F.f.10.1.Seq N39216 8723 RTA00000607F.o.13.2.Seq THC2336198724 RTA00000622F.c.12.1.Seq THC118482 8725 RTA00000625F.b.07.1.SeqTHC223154 8726 RTA00000587F.j.01.1.Seq H63018 8727RTA00000608F.i.15.1.Seq THC216448 8728 RTA00000592F.j.06.1.Seq THC1482158729 RTA00000589F.b.14.1.Seq THC158020 8730 RTA00000633F.g.19.1.SeqTHC202541 8731 RTA00000620F.o.07.1.Seq THC155200 8732RTA00000586F.p.01.1.Seq AA558590 8733 RTA00000630F.1.10.1.Seq THC2047488734 RTA00000626F.c.13.1.Seq AA159259 8735 RTA00000591F.m.06.1.SeqTHC227858 8736 RTA00000630F.i.11.1.Seq THC228806 8737RTA00000621F.h.08.1.Seq THC163604 8738 RTA00000589F.d.10.1.Seq THC1770768739 RTA00000597F.p.01.1.Seq THC210746 8740 RTA00000619F.c.13.1.SeqR57955 8741 RTA00000607F.c.07.2.Seq THC208762 8742RTA00000595F.b.02.1.Seq THC233682 8743 RTA00000631F.h.04.1.Seq THC2232818744 RTA00000596F.p.18.1.Seq THC197103 8745 RTA00000586F.o.13.1.SeqTHC222729 8746 RTA00000610F.p.17.1.Seq EST19015 8747RTA00000596F.c.05.1.Seq EST72617 8748 RTA00000632F.j.19.1.Seq THC907418749 RTA00000607F.e.23.2.Seq AA639216 8750 RTA00000628F.b.19.1.SeqTHC118075 8751 RTA00000609F.d.13.1.Seq THC195579 8752RTA00000621F.k.03.1.Seq EST70278 8753 RTA00000592F.1.04.1.Seq THC919418754 RTA00000592F.k.09.1.Seq THC229803 8755 RTA00000622F.e.17.1.SeqR57425 8756 RTA00000628F.g.13.1.Seq THC176706 8757RTA00000592F.k.23.1.Seq THC232202 8758 RTA00000609F.m.04.2.Seq AA5076118759 RTA00000626F.b.04.1.Seq EST69420 8760 RTA00000591F.m.01.1.SeqH41850 8761 RTA00000608F.n.23.1.Seq THC214886 8762RTA00000583F.d.19.1.Seq THC229251 8763 RTA00000621F.p.15.1.Seq THC2124508764 RTA00000583F.n.05.1.Seq AA252468 8765 RTA00000597F.f.17.1.SeqTHC219322 8766 RTA00000606F.1.10.1.Seq THC225232 8767RTA00000618F.n.14.1.Seq THC216591 8768 RTA00000612F.h.05.3.Seq THC1582508769 RTA00000619F.a.24.1.Seq AA437370 8770 RTA00000617F.k.13.1.SeqAA244445 8771 RTA00000623F.h.07.1.Seq THC212330 8772RTA00000620F.e.01.1.Seq THC167493 8773 RTA00000620F.h.10.1.Seq THC2324568774 RTA00000589F.e.21.2.Seq THC208239 8775 RTA00000626F.b.22.1.SeqTHC225644 8776 RTA00000620F.i.16.1.Seq AA536090 8777RTA00000613F.c.17.1.Seq THC92470 8778 RTA00000621F.c.12.1.Seq THC1562448779 RTA00000618F.b.17.1.Seq THC209838 8780 RTA00000585F.d.16.1.SeqTHC211870 8781 RTA00000592F.a.06.1.Seq THC233200 8782RTA00000583F.p.08.1.Seq THC196844 8783 RTA00000622F.h.21.1.Seq EST126988784 RTA00000591F.h.03.1.Seq THC213771 8785 RTA00000620F.g.22.1.SeqTHC224063 8786 RTA00000588F.l.20.2.Seq R84876 8787RTA00000614F.a.20.1.Seq R84876 8788 RTA00000611F.n.14.3.Seq THC2007428789 RTA00000619F.f.23.1.Seq THC227573 8790 RTA00000608F.g.24.1.SeqT93977 8791 RTA00000595F.o.01.2.Seq EST61392 8792RTA00000608F.b.23.1.Seq THC161665 8793 RTA00000606F.o.23.1.Seq AA4646458794 RTA00000588F.i.22.3.Seq THC162216 8795 RTA00000610F.i.13.1.SeqAA595068 8796 RTA00000608F.b.15.1.Seq EST11866 8797RTA00000597F.e.16.1.Seq N88730 8798 RTA00000610F.h.13.1.Seq THC1958958799 RTA00000611F.h.21.2.Seq EST46722 8800 RTA00000584F.b.06.1.SeqEST02998 8801 RTA00000584F.b.06.2.Seq EST02998 8802RTA00000608F.j.05.1.Seq EST60433 8803 RTA00000588F.b.03.1.Seq THC164651

The contiged sequences (SEQ ID NOS: 8707-8803) thus represent longersequences that encompass a polynucleotide sequence of the invention. Thecontiged sequences were then translated in all three reading frames todetermine the best alignment with individual sequences using the BLASTprograms as described above. The sequences were masked using the XBLASTprogram for masking low complexity as described above in Example 27.Several of the contiged sequences were found to encode polypeptideshaving characteristics of a polypeptide belonging to a known proteinfamilies (and thus represent new members of these protein families)and/or comprising a known functional domain (Table 42B, inserted priorto claims). Thus the invention encompasses fragments, fusions, andvariants of such polynucleotides that retain biological activityassociated with the protein family and/or functional domain identifiedherein.

Descriptions of the profiles for the indicated protein families andfunctional domains are provided 3 above. A description of the profilefor PR55 is provided below.

Protein Phosphatase 2A Regulatory Subunit PR55 (PR55). Several of thecontigs correspond to a sequence encoding a protein comprising a proteinphosphatase 2A (PP2A) regulatory subunit PR55. PP2A is aserine/threonine phosphatase involved in many aspects of cellularfunction including the regulation of metabolic enzymes and proteinsinvolved in signal transduction. PP2A is a trimeric enzyme comprising acore composed of a catalytic subunit associated with a 65 Kd regulatorysubunit (PR65, also called subunit A). This complex associates with athird variable subunit (subunit B), which confers distinct properties tothe holoenzyme (Mayer-Jaekel et al. Trends Cell Biol. (1994) 4:287-291).One of the forms of the variable subunit is a 55 Kd protein (PR55) whichis highly conserved in mammals and may facilitate substrate recognitionor targeting the enzyme complex to the appropriate subcellularcompartment. The PR55 subunit comprises two conserved sequences of 15residues; one located in the N-terminal region, the other in the centerof the protein.

Those skilled in the art will recognize, or be able to ascertain, usingnot more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such specific embodimentsand equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Deposit Information. The following materials were deposited with theAmerican Type Culture Collection (CMCC=Chiron Master CultureCollection). TABLE 59 Cell Lines Deposited with ATCC CMCC Cell LineDeposit Date ATCC Accession No. Accession No. KM12L4-A Mar. 19, 1998CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15,1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containingspecific clones, were assigned an “ES” number (internal reference) anddeposited with the ATCC. Table 60 below provides the ATCC Accession Nos.of the ES deposits, all of which were deposited on or before May 13,1999. The names of the clones contained within each of these depositsare provided in the tables numbered 61-63 (inserted before the claims).TABLE 60 Pools of Clones and Libraries Deposited with ATCC on or beforeMay 14, 1999 ES # ATCC Accession # 34 35 36 37 38 39 40 41 42 43 44 4546 47 48 49 50 51 52 53 54

The deposits described herein are provided merely as convenience tothose of skill in the art, and is not an admission that a deposit isrequired under 35 U.S.C. §112. The sequence of the polynucleotidescontained within the deposited material, as well as the amino acidsequence of the polypeptides encoded thereby, are incorporated herein byreference and are controlling in the event of any conflict with thewritten description of sequences herein. A license may be required tomake, use, or sell the deposited material, and no such license isgranted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones. Where theATCC deposit is composed of a pool of cDNA clones or a library of cDNAclones, the deposit was prepared by first transfecting each of theclones into separate bacterial cells. The clones in the pool or librarywere then deposited as a pool of equal mixtures in the compositedeposit. Particular clones can be obtained from the composite depositusing methods well known in the art. For example, a bacterial cellcontaining a particular clone can be identified by isolating singlecolonies, and identifying colonies containing the specific clone throughstandard colony hybridization techniques, using an oligonucleotide probeor probes designed to specifically hybridize to a sequence of the cloneinsert (e.g., a probe based upon unmasked sequence of the encodedpolynucleotide having the indicated SEQ ID NO). The probe should bedesigned to have a T_(m) of approximately 80° C. (assuming 2° C. foreach A or T and 4° C. for each G or C). Positive colonies can then bepicked, grown in culture, and the recombinant clone isolated.Alternatively, probes designed in this manner can be used to PCR toisolate a nucleic acid molecule from the pooled clones according tomethods well known in the art, e.g., by purifying the cDNA from thedeposited culture pool, and using the probes in PCR reactions to producean amplified product having the corresponding desired polynucleotidesequence. TABLE 61 Deposits of Pooled Clones ES34 ES35 ES36 ES37M00006992C:G02 M00005468A:D08 M00005452C:A02 M00022171D:B08M00006756D:E10 M00021892B:H03 M00001382C:C09 M00008061A:F02M00003984C:F04 M00001390A:C06 M00004841C:B09 M00003820C:A09M00007125D:E03 M00022074D:F11 M00001441D:H05 M00022109B:A11M00006650A:A10 M00005460B:D02 M00022716D:D08 M00005342D:F03M00001452B:H06 M00022423B:D03 M00022828C:E04 M00022070B:C10M00022972D:C10 M00007140A:F11 M00004350B:F06 M00006966B:B09M00022305C:A01 M00004081B:C11 M00005685B:D08 M00022381C:C12M00007010B:H01 M00005480A:H12 M00004190A:A09 M00003991B:B05M00021946D:C11 M00008015D:E09 M00004054D:D02 M00022404D:G05 ES38 ES39ES40 ES41 M00021912B:H11 M00007118B:B04 M00006993B:B09 M00007974B:C11M00005378C:A10 M00007019A:B01 M00004242C:C01 M00021860B:G06M00022578C:B07 M00021682B:D12 M00007986C:C05 M00006927C:F12M00005513A:D08 M00005411D:A03 M00004115A:G09 M00022582C:E12M00022176C:A08 M00006641C:H02 M00022600C:A06 M00006618C:G08M00006822D:F07 M00007041B:C05 M00005384A:A01 M00005450B:B01M00004031A:B04 M00005444B:E11 M00021667D:E03 M00001417B:E01M00021927D:D12 M00022745B:G02 M00008078C:C06 M00003825B:A05M00001553D:B06 M00022685A:F11 M00007985A:B09 M00001370B:B04M00022404B:H05 M00004446A:G01 M00007953B:B03 M00006727B:E09 ES42 ES43ES44 ES45 M00001478A:B06 M00006923B:H08 M00006615B:F05 M00005468D:F04M00003972B:A11 M00005377D:F11 M00005486C:B03 M00006720C:C11M00005477C:D08 M00006640B:H09 M00007124C:A11 M00005817D:E12M00006745A:A01 M00005404C:F02 M00006995D:A03 M00001669B:A03M00007090B:A02 M00004030A:G12 M00007149D:G06 M00003998A:G12M00007152A:B04 M00006704D:D03 M00006990D:D06 M00004045A:B12M00006953B:H10 M00006810D:A05 M00005530B:E04 M00004130D:E04M00005399D:B02 M00005481C:A05 M00003918C:E07 M00004160A:D07M00006987B:F04 M00005411A:C07 M00007163A:B10 M00001655A:F07M00005772A:F03 M00003970A:G10 M00005485C:A03 M00001468D:D11 ES46M00004217A:A05 M00004183D:B07 M00001415D:A05 M00004158C:F03M00004031D:G02

TABLE 62 Library Deposits ES47 ES48 ES49 ES50 M00001399D:F09M00004217D:G10 M00004508A:G12 M00021653A:G07 M00001455A:C03M00004218C:G10 M00004508B:G02 M00021654C:A02 M00001456C:F02M00004252D:H08 M00001432B:H08 M00021660C:G04 M00001487D:G03M00004253B:A10 M00001432C:G01 M00021665A:D04 M00001539B:B01M00004253B:F06 M00003992D:G01 M00021670B:G11 M00001565A:A02M00004253C:E10 M00005326B:F03 M00021678A:B08 M00001572C:E07M00004260A:B07 M00005332A:H10 M00021680B:C01 M00001582D:B10M00004260C:A12 M00005342A:C04 M00021681C:B10 M00001584C:A03M00004260C:E10 M00005342A:D04 M00021690D:E05 M00001586A:F09M00001339B:A03 M00005349B:G01 M00021692A:E03 M00001588D:H08M00001342C:A04 M00005352B:D02 M00021692C:E06 M00001610B:A01M00001344D:G11 M00005354C:E02 M00021694B:A07 M00001618B:F02M00001345A:A12 M00005356A:D09 M00021698B:B12 M00001618C:E06M00001347A:G06 M00005359D:G07 M00021828A:C08 M00001621C:A04M00001347B:H01 M00005378A:A08 M00021841C:D07 M00001626B:H05M00001353B:D11 M00005383D:D06 M00021859A:D04 M00001641B:G05M00001355B:A01 M00005383D:E07 M00021861C:A02 M00001648C:F06M00001358D:D09 M00005385C:G05 M00021862A:A04 M00001649D:H05M00001359A:B07 M00005388D:F09 M00021862D:F01 M00001656D:F11M00001362A:C10 M00005390B:G10 M00021886D:E04 M00001660A:F10M00001362B:A09 M00005397C:B03 M00021897B:A06 M00001669A:H11M00001365D:D12 M00005399A:D01 M00021905A:G05 M00003741A:E01M00001365D:H09 M00005409D:C02 M00021905B:A01 M00003745C:E03M00001370A:G09 M00005415C:G08 M00021906C:G11 M00003746A:E01M00001370B:B12 M00005417A:E10 M00021910A:C10 M00003748B:B06M00001374D:D09 M00005442D:C05 M00021927A:C11 M00003749B:C08M00001376B:C11 M00005446A:G01 M00021927B:F01 M00003749D:G07M00001377A:D03 M00005446C:D12 M00021932C:C05 M00003752A:B06M00001377A:E01 M00005454C:H12 M00021932C:G10 M00003752D:D09M00001377C:B08 M00005455A:D01 M00021947A:C01 M00003753C:B01M00001387A:A04 M00005455A:G03 M00021952B:F11 M00003754C:F01M00001387D:C07 M00005462C:B02 M00021954A:A03 M00003756C:C08M00001389B:B06 M00005469D:C11 M00021964A:C04 M00003759A:E10M00001390A:H01 M00005480C:B12 M00021967D:E08 M00003762A:D11M00001399C:E10 M00005483D:A12 M00021977D:E02 M00003763B:D03M00001401D:D04 M00005484A:D09 M00021978A:F08 M00003763D:F06M00001402D:C07 M00005491B:C03 M00021982C:F08 M00003765D:E02M00001402D:H03 M00005493B:C08 M00021983B:B03 M00003766B:G04M00001403B:A01 M00005494D:F11 M00021983D:B10 M00003767C:F04M00001405D:F05 M00005496C:A01 M00022005C:G03 M00003769B:A04M00001406C:A11 M00005496D:A10 M00022032A:E07 M00003769D:G12M00001406D:H01 M00005497B:H07 M00022049A:A02 M00003770D:C07M00001407B:A08 M00005497C:C07 M00022049A:D06 M00003771A:G09M00001407D:H11 M00005497C:C12 M00022054D:C05 M00003771D:A10M00001411A:D01 M00005497C:E03 M00022064C:H07 M00003773A:C09M00001411C:G02 M00005498B:F08 M00022067D:C05 M00003773B:E09M00001412A:A11 M00005498C:G05 M00022068B:H11 M00003773B:G08M00001415D:E12 M00005508B:B04 M00022068D:D12 M00003773C:G06M00001417C:E02 M00005524C:B01 M00022069D:G02 M00003773D:C02M00001421A:H07 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M00003825C:B02M00001435C:G08 M00005703A:C08 M00022150A:H06 M00003825C:B12M00001435D:A06 M00005704A:B11 M00022153D:D11 M00003833B:A11M00001436D:C10 M00005708D:B03 M00022157A:F12 M00003834A:A03M00001437B:B05 M00005710A:C08 M00022157B:A10 M00003835D:H05M00001438C:H05 M00005720A:D03 M00022169D:C02 M00003839D:G06M00001439B:F10 M00005722D:G03 M00022170D:H09 M00003841A:E09M00001439C:A01 M00005743B:F02 M00022175A:A11 M00003841B:D05M00001439C:G06 M00005763B:H09 M00022176A:E08 M00003843A:B01M00001442A:D08 M00005765C:C04 M00022178D:H01 M00003844C:D04M00001443D:A01 M00005810C:D04 M00022183A:G03 M00003844C:H05M00001444A:A09 M00005813D:F06 M00022189A:A01 M00003846B:H02M00001446D:B10 M00005818C:E08 M00022198A:C12 M00003850B:D11M00001452D:E05 M00005818C:G01 M00022199C:F03 M00003852D:D03M00001453D:F09 M00006576D:F11 M00022202C:F11 M00003859C:B09M00001463C:A01 M00006577B:H12 M00022206B:G06 M00003868D:F02M00001466C:F02 M00006587A:H08 M00022212C:C02 M00003868D:F07M00001471C:G03 M00006594A:E08 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M00003963B:D12M00003864B:A04 M00006850C:G07 M00022386B:D11 M00003973A:C05M00003864D:G05 M00006851C:H09 M00022386C:A04 M00003973B:H06M00003992C:G01 M00006863B:E06 M00022386C:D07 M00003976D:D12M00003992D:G01 M00006866C:F03 M00022399C:A10 M00003977C:A08M00003994C:C11 M00006867C:E07 M00022407C:H11 M00003980B:F12M00003996D:C04 M00006868D:E02 M00022411D:G09 M00003980C:G10M00003997D:D07 M00006870C:H06 M00022412A:C08 M00003981C:E04M00003998A:D03 M00006873B:G11 M00022444A:A11 M00003983C:E07M00003998C:H10 M00006875A:A02 M00022449C:B01 M00003987D:F06M00003999C:C12 M00006877B:E05 M00022452C:B03 M00004027A:B10M00004046A:F04 M00006879A:H11 M00022457C:B01 M00004027C:H01M00004051C:D02 M00006882A:D01 M00022495C:G05 M00004028C:B04M00004052C:A08 M00006901D:A11 M00022504B:E03 M00004030B:B02M00004052C:B05 M00006907C:D03 M00022505D:A12 M00004030B:C05M00004054B:G02 M00006907D:C07 M00022509D:F06 M00004035D:E04M00004054D:A03 M00006912B:E01 M00022527A:E05 M00004036B:F09M00004055B:F06 M00006921B:E01 M00022527D:B03 M00004036C:D01M00004058B:C11 M00006960D:E06 M00022531B:D07 M00004037A:A07M00004058C:E08 M00006963A:H11 M00022535D:B11 M00004037B:B05M00004059A:G09 M00006966C:B07 M00022535D:C04 M00004038C:C05M00004060C:A02 M00006972A:F10 M00022536B:B04 M00004038C:D12M00004060D:A07 M00006973C:E11 M00022551A:G03 M00004039D:D03M00004063C:B11 M00006973D:E11 M00022556B:C04 M00004040B:B09M00004143A:G12 M00006974B:F06 M00022556B:G02 M00004040C:G12M00004143A:H07 M00006976C:E09 M00022562C:H10 M00004040D:B05M00004145C:A03 M00007014C:B07 M00022578B:G05 M00004041B:F01M00004146D:A07 M00007015C:G05 M00022578D:F03 M00004041D:E06M00004147A:G03 M00007016C:E06 M00022583B:E05 M00004043D:C10M00004149B:H12 M00007041B:G01 M00022587C:G04 M00004069D:G02M00004153D:E06 M00007042A:E07 M00022594B:H12 M00004071A:H03M00004154D:F11 M00007043A:B05 M00022598A:F11 M00004073D:B11M00004159D:C04 M00007046A:D02 M00022599D:E07 M00004076D:B03M00004166B:E10 M00007047B:D01 M00022604B:C11 M00004081C:A01M00004166C:A03 M00007051D:D09 M00022607B:A04 M00004084C:G04M00004166D:G07 M00007053B:H03 M00022613D:C04 M00004085B:G06M00004196C:G05 M00007058A:C02 M00022651D:C06 M00004087C:F05M00004234B:E03 M00007062A:D03 M00022666C:H11 M00004091A:E01M00004234B:G06 M00007099A:F09 M00022681C:H02 M00004091B:C12M00004236D:E07 M00007100C:D01 M00022682A:F12 M00004091B:G04M00004236D:F04 M00007112B:C06 M00022698C:E06 M00004091C:F04M00004240D:A07 M00007105D:C07 M00022701B:B12 M00004091D:D09M00004242C:C02 M00007121A:A05 M00022708A:C08 M00004092A:C03M00004244B:A02 M00007122A:G11 M00022708D:G10 M00004092A:D04M00004245A:G09 M00007122B:A11 M00022725C:E09 M00004093D:D09M00004245C:A03 M00007127B:A04 M00022726A:A06 M00004101D:A03M00004247A:E01 M00007129A:G10 M00022730A:E04 M00004103B:C07M00004247B:C11 M00007130B:B03 M00022737A:C08 M00004107C:A01M00004248A:G08 M00007132D:G08 M00022763A:E10 M00004114C:F02M00004263D:F06 M00007134C:F07 M00022824C:H11 M00004115A:F01M00004272D:D02 M00007137D:C10 M00022835C:E06 M00004117B:F01M00004273D:E11 M00007140D:C12 M00022854D:H07 M00004120A:C02M00004277D:C08 M00007150A:C09 M00022856A:D02 M00004126B:G02M00004281B:B05 M00007150A:H06 M00022856B:F04 M00004129A:H08M00004283C:D03 M00007154A:E04 M00022856C:B11 M00004130C:A09M00004285B:E01 M00007163A:F11 M00022893C:H11 M00004133D:A01M00004297D:E08 M00007163B:A12 M00022897A:F04 M00004178B:F06M00004298B:D04 M00007166B:E06 M00022900D:E08 M00004180B:F04M00004308A:E06 M00007170D:A10 M00022900D:G03 M00004184B:F11M00004324B:D09 M00007172A:A05 M00004191B:G01 M00004328A:H06M00007172D:C08 M00004193A:C07 M00004329C:F11 M00007188A:D03M00004193C:H01 M00004331D:H08 M00007189D:A09 M00004199D:C02M00004332C:E09 M00007193D:A04 M00004200A:A09 M00004337D:G08M00007195B:B02 M00004200A:G06 M00004345A:H06 M00007198C:A10M00004200D:A07 M00004383A:F02 M00007199D:B07 M00004201D:C11M00004385C:B11 M00007204C:F09 M00004201D:E12 M00004388C:D05M00007929B:H10 M00004202B:A02 M00004406A:H03 M00007961A:B01M00004204A:D04 M00004408D:A10 M00007964B:D10 M00004204A:D10M00004410A:E03 M00007971A:B04 M00004204B:A04 M00004412B:E03M00007977C:E08 M00004210A:B09 M00004421A:G04 M00007995D:E06M00004216D:E10 M00004447D:D10 M00008074D:C01 M00004217A:A11M00004460B:H09 M00008094A:E10 M00004465C:B10 M00021611D:D05M00004465C:B12 M00021611D:H03 M00004467A:F09 M00021614B:G12M00004467D:F09 M00021618D:D07 M00004491D:D07 M00021624A:D07M00004497C:E09 M00021624B:A03 M00004501A:G06 M00021625A:C07M00004506C:H10 M00021629D:D05

TABLE 63 Library Deposits ES51 ES52 ES53 ES54 M00001448A:D05M00001439B:E02 M00006621A:G10 M00021640A:G03 M00001458B:F06M00001443A:E02 M00006626A:G11 M00021657B:C08 M00001530A:D11M00001443D:C03 M00006629D:D04 M00021690B:B06 M00001563C:D06M00001444A:G12 M00006630B:H06 M00021690C:B07 M00001564C:D04M00001445B:E03 M00006631D:B02 M00022071C:C09 M00001569B:F04M00001451B:H11 M00006631D:C04 M00022081C:B11 M00001575A:H02M00001452B:F09 M00006631D:E09 M00022085C:A07 M00001589C:D12M00001488B:H02 M00006635C:B10 M00022091B:B07 M00001589D:G10M00001491D:E07 M00006636A:E06 M00022122D:D06 M00001590D:A07M00001496C:H10 M00006636D:A05 M00022150D:D11 M00001598C:D10M00001499A:D01 M00006636D:F11 M00022154A:C01 M00001599A:H09M00001499A:D05 M00006640A:B01 M00022170D:H07 M00001609A:B12M00001499B:H05 M00006640B:F05 M00022365A:A01 M00001614C:G04M00001500B:H07 M00006640D:H08 M00022389B:H04 M00001626C:C10M00001504C:H11 M00006641A:B03 M00022439A:E07 M00001634C:E12M00001506D:A11 M00006643A:E10 M00022449D:F06 M00001639A:A04M00001543A:D03 M00006644C:E09 M00022458B:E06 M00001640A:F02M00001543A:F01 M00006648C:E04 M00022474A:H09 M00001640A:F04M00001548C:A09 M00006650A:B11 M00022480B:E07 M00001647C:C07M00001555D:F11 M00006656C:C10 M00022489C:A08 M00001649B:E08M00001557B:D10 M00006664B:B04 M00022490C:A08 M00001654D:F06M00001597A:C07 M00006664D:H09 M00022490C:C01 M00001658B:C07M00001604B:D09 M00006665A:F07 M00022493C:B07 M00001659D:G08M00001605D:G01 M00006665B:D10 M00022493C:C06 M00001663C:C03M00001621D:B09 M00006674B:F04 M00022498C:C08 M00001675C:B03M00001622C:F06 M00006676B:F11 M00022514A:D04 M00001677A:A06M00001624A:A09 M00006676D:D11 M00022515D:C04 M00001677A:A12M00001640D:C10 M00006679C:D07 M00022549B:G07 M00001678D:A12M00001645B:C09 M00006681C:G04 M00022557B:A08 M00001679C:F03M00003782D:F04 M00006695B:F08 M00022565C:H02 M00001681A:H09M00003783C:A06 M00006698B:E06 M00022578D:A08 M00001687C:A06M00003786D:C06 M00006699B:C07 M00022597B:F11 M00001693D:F07M00003787B:D07 M00006705B:D02 M00022599A:C03 M00003746B:E12M00003787D:A06 M00006712B:H10 M00022661B:E11 M00003766A:G09M00003864C:D09 M00006717A:D04 M00022661D:H01 M00003795A:B01M00003993A:E12 M00006721C:G07 M00022666B:E12 M00003796C:H03M00003997B:H04 M00006725A:A03 M00022674D:G04 M00003797D:E10M00003997D:G11 M00006725A:B03 M00022718D:G05 M00003799B:D02M00004047B:G09 M00006727B:G08 M00022725C:B03 M00003809B:D08M00004048D:A07 M00006728C:B06 M00022727B:C05 M00003811B:E07M00004049D:G04 M00006737C:A08 M00022728A:A09 M00003812B:F08M00004050A:F02 M00006738A:E05 M00022730D:E10 M00003812D:E08M00004051C:D10 M00006739B:B10 M00022735B:B01 M00003815C:A06M00004058B:F12 M00006739B:B12 M00022745A:B04 M00003815D:D01M00004060C:A11 M00006739C:H07 M00022856B:D07 M00003816C:F10M00004064A:B12 M00006743B:G12 M00022901D:C09 M00003818C:E09M00004066A:E12 M00006744C:C06 M00022902D:D03 M00003819A:B09M00004067C:D08 M00006745D:E08 M00022953B:C07 M00003819C:E04M00004134A:F08 M00006751A:F03 M00022960D:E08 M00003820A:H04M00004134A:H04 M00006758D:C01 M00022963A:D11 M00003820D:E02M00004134C:B11 M00006760D:G12 M00022968A:F02 M00003824B:D06M00004140B:B01 M00006763B:B11 M00022980B:E11 M00003825B:D12M00004143C:F08 M00006769D:A04 M00022980C:A09 M00003826B:D01M00004144D:B06 M00006770B:C05 M00022993A:F02 M00003829A:E02M00004152C:E01 M00006771A:E06 M00023003C:A03 M00003832B:G03M00004159D:H07 M00006771A:H07 M00023011A:A06 M00003833D:D06M00004160A:A01 M00006771B:A09 M00023021A:H08 M00003835A:E03M00004161B:A12 M00006771B:F03 M00023023A:B12 M00003837C:F05M00004163A:D11 M00006774D:C01 M00023028A:A02 M00003839C:B05M00004164D:D02 M00006777B:D10 M00023033A:E10 M00003845A:A05M00004165C:E09 M00006779B:A11 M00023034C:E05 M00003846D:C12M00004166A:F02 M00006779D:D03 M00023036D:C04 M00003857C:A03M00004167C:F10 M00006780A:H12 M00023094A:C04 M00003858A:D01M00004169A:B11 M00006789C:F04 M00023103A:E11 M00003860B:A07M00004200B:B04 M00006790D:A05 M00006754B:D05 M00003868B:C07M00004222A:H10 M00006796A:H10 M00003881D:D09 M00004223D:D07M00006797B:D12 M00003883D:C03 M00004225D:F01 M00006801A:G05M00003884B:E06 M00004228C:D11 M00006805A:E11 M00003886C:D10M00004229C:G11 M00006805A:H09 M00003903C:A12 M00004239C:A07M00006805B:C04 M00003912C:H01 M00004239C:C09 M00006807D:D08M00003915B:G07 M00004240D:E06 M00006813A:C04 M00003920D:D09M00004241B:B01 M00006822D:D05 M00003926B:E03 M00004243C:E10M00006825C:D06 M00003934D:F01 M00004266A:F10 M00006831B:B04M00003958C:C10 M00004266B:H06 M00006832A:F05 M00003965A:F07M00004268C:F08 M00006832D:F10 M00003972C:F02 M00004268D:G07M00006833B:E11 M00003974B:A04 M00004269A:B11 M00006872B:G01M00003974C:A05 M00004269D:E08 M00006875D:D10 M00003975B:H09M00004276C:E12 M00006879D:A10 M00003976C:C05 M00004277B:C06M00006882D:F03 M00003980C:A11 M00004277C:H11 M00006884D:D06M00003987A:C07 M00004279D:E02 M00006908C:A05 M00003988B:C10M00004281B:B03 M00006921B:C02 M00003988C:A06 M00004284B:F07M00006921B:E03 M00003989C:F01 M00004287B:B12 M00006949B:F03M00004028C:D01 M00004287C:B06 M00006960A:G11 M00004029A:E01M00004297D:B08 M00006966D:G03 M00004030A:E09 M00004332B:D02M00006974B:D06 M00004031A:G05 M00004332B:E11 M00007013B:F02M00004032D:D03 M00004346B:D06 M00007014D:C05 M00004033C:D10M00004389C:E01 M00007014D:D04 M00004034A:E08 M00004403A:B05M00007030A:G01 M00004035A:A10 M00004407D:B09 M00007030C:F08M00004035B:H11 M00004419D:G01 M00007053B:C07 M00004035D:C05M00004449D:H01 M00007065B:B12 M00004037B:A09 M00004463C:F11M00007065D:C01 M00004037C:C05 M00004466A:E09 M00007075C:D08M00004037D:B05 M00004469A:C12 M00007085A:B07 M00004044A:F08M00004470C:A02 M00007118C:G02 M00004068A:F02 M00004498B:E01M00007119B:H10 M00004068B:D04 M00004509A:H02 M00004824C:G09M00004068D:B01 M00004605C:A09 M00004826A:E09 M00004069B:B01M00004609C:C11 M00004839C:B01 M00004073D:E01 M00001378B:F06M00004840C:F02 M00004075A:G10 M00005294C:G08 M00004840C:H05M00004075C:C09 M00005294D:H02 M00004845D:E11 M00004076A:E02M00005330C:F09 M00004846A:D02 M00004077D:D10 M00005333C:C08M00004846D:H09 M00004078A:F03 M00005342B:G10 M00004854A:C09M00004078C:A08 M00005352C:G09 M00004858D:E06 M00004084A:D11M00005352D:E06 M00004999A:F01 M00004086A:A03 M00005353B:B09M00004999B:D12 M00004086D:A07 M00005359B:G01 M00004999D:E01M00004088A:F12 M00005359D:H08 M00005004B:C11 M00004089A:F02M00005377A:A04 M00005005C:E06 M00004089A:G03 M00005377A:D05M00005009B:A02 M00004093A:F03 M00005385C:D08 M00005015D:D11M00004097C:A03 M00005388A:F07 M00005457D:C08 M00004102B:B04M00005388D:B11 M00005519B:H04 M00004102C:F07 M00005392C:C04M00005519C:F08 M00004103B:C09 M00005393A:E11 M00005531B:A03M00004103C:F11 M00005394A:G07 M00005535B:F06 M00004104A:H09M00005396B:C04 M00005587B:H02 M00004104D:C09 M00005399B:F02M00005685A:A04 M00004108A:D04 M00005400A:D02 M00005706D:A09M00004109B:A01 M00005403D:E11 M00005711A:H01 M00004126D:B11M00005406D:B08 M00005798B:C11 M00004133C:B02 M00005411D:E05M00005799C:C12 M00004182D:H03 M00005415D:G02 M00005805D:E06M00004183A:D06 M00005417C:E10 M00005827B:H08 M00004186B:E05M00005419A:D05 M00005828D:C09 M00004187C:H09 M00005419C:D09M00005837A:D12 M00004188A:E05 M00005443D:C12 M00006751B:B11M00004188A:E10 M00005447B:D02 M00006754B:D05 M00004190A:C12M00005448D:E08 M00006756B:B08 M00004190C:G07 M00005450A:A02M00006757D:E04 M00004190D:A10 M00005450A:B10 M00006758A:B12M00004190D:G12 M00005450D:D02 M00006758D:C04 M00004198D:H04M00005451A:E03 M00006834A:C08 M00004202B:F04 M00005456B:B07M00006835B:F04 M00004202B:G09 M00005456B:E03 M00006837C:G06M00004206C:G11 M00005460A:B10 M00006841D:A08 M00004213A:H12M00005465C:H02 M00006855C:H02 M00004214A:D03 M00005466A:F12M00006855D:H02 M00004218D:F12 M00005468B:D04 M00006859A:F06M00004249C:E12 M00005470B:E01 M00006860B:H01 M00004249D:G02M00005473D:E10 M00006886A:D06 M00004252D:A07 M00005483A:F05M00006893C:B02 M00004253D:F09 M00005483D:A02 M00006893C:F02M00004257C:A08 M00005487A:H01 M00006895D:E10 M00004262C:C01M00005489A:F06 M00006917C:E07 M00001339B:E05 M00005493B:A12M00006919B:C03 M00001341A:A11 M00005493B:E01 M00006923C:B01M00001346A:B09 M00005497C:C10 M00006926A:H11 M00001346B:A07M00005505A:C08 M00006934A:G02 M00001346B:G03 M00005508A:H01M00006936B:E09 M00001346C:B07 M00005510B:D06 M00006936B:F10M00001348A:G04 M00005528D:H06 M00006937B:F07 M00001348D:H08M00005534A:G06 M00006937B:G09 M00001352C:E01 M00005539D:G07M00006939B:E05 M00001362B:H09 M00005571A:E11 M00006953D:H11M00001370A:B01 M00005619C:H10 M00006980A:F02 M00001370B:D04M00005625D:C03 M00006986C:G11 M00001374C:C09 M00005626A:B11M00006989B:C11 M00001376A:H02 M00005635B:A06 M00006990B:H09M00001378B:F06 M00005635C:F11 M00006991A:E07 M00001380C:D10M00005636C:D11 M00006991D:G07 M00001383C:C07 M00005637D:C05M00006995C:A02 M00001384A:C09 M00005641B:E02 M00006997B:E06M00001391D:A07 M00005645D:F08 M00006997D:B03 M00001391D:A09M00005646C:B09 M00007006D:D04 M00001396C:G02 M00005646D:B03M00007010B:C11 M00001397A:F10 M00005655D:C04 M00007010B:H03M00001397B:E02 M00005703C:B01 M00007012B:D07 M00001397B:H11M00005720B:D09 M00007031C:D01 M00001399D:F01 M00005722A:E09M00007032A:F11 M00001400D:B08 M00005762D:A01 M00007033A:H05M00001402C:E09 M00005783A:C05 M00007033D:F04 M00001406A:G12M00005812C:F10 M00007036A:D02 M00001406D:B06 M00006581C:D02M00007037B:D04 M00001408A:B02 M00006581D:H08 M00007084B:A05M00001409C:D01 M00006582A:B09 M00007093A:F09 M00001411C:F02M00006582D:E05 M00007099C:F09 M00001411D:C01 M00006592A:D03M00007101A:A11 M00001412D:C03 M00006594D:F09 M00007107A:D11M00001417B:C07 M00006596A:F07 M00007121C:H01 M00001417C:A09M00006601D:F04 M00007129A:E04 M00001418A:C02 M00006604C:H10M00007132B:B11 M00001421C:A03 M00006607B:E03 M00007134B:G07M00001426A:C02 M00006607B:F04 M00007146D:G01 M00001427A:C05M00006615D:F04 M00007148B:C06 M00001433A:F04 M00006616C:H09M00007160C:B08 M00001434C:D05 M00006616D:C08 M00007161A:H03M00001435C:H05 M00006617B:D09 M00007192C:H08 M00001438A:H10M00006619B:C11 M00007200B:C02 M00001438B:H06 M00021619B:G10

Example 41 Source of Biological Materials and Overview of NovelPolynucleotides Expressed by the Biological Materials

cDNA libraries were constructed from either human colon cancer cell lineKm12L4-A (Morikawa, et al., Cancer Research (1988) 48:6863), KM12C(Morikawa et al. Cancer Res. (1988) 48:1943-1948), or MDA-MB-231(Brinkley et al. Cancer Res. (1980) 40:3118-3129) was used to constructa cDNA library from mRNA isolated from the cells. Sequences expressed bythese cell lines were isolated and analyzed; most sequences were about275-300 nucleotides in length. The KM12L4-A cell line is derived fromthe KM12C cell line. The KM12C cell line, which is poorly metastatic(low metastatic) was established in culture from a Dukes' stage B₂surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). TheKML4-A is a highly metastatic subline derived from KM12C (Yeatman et al.Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am.Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived celllines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as amodel cell line for the study of colon cancer (see, e.g., Moriakawa etal., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman etal., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246).The MDA-MB-231 cell line was originally isolated from pleural effusions(Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastaticpotential, and forms poorly differentiated adenocarcinoma grade II innude mice consistent with breast carcinoma.

Example 42 Differential Expression of Polynucleotides of the Invention:Description of Libraries and Detection of Differential Expression

The relative expression levels of various polynucleotides isolated fromthe Example 41 were assessed in several libraries prepared from varioussources, including cell lines and patient tissue samples. Table 64provides a summary of these libraries, including the shortened libraryname (used hereafter), the mRNA source used to prepared the cDNAlibrary, the “nickname” of the library that is used in the tables below(in quotes), and the approximate number of clones in the library. TABLE64 Description of cDNA Libraries No. of Library Clones in (lib #)Description Library 1 Human Colon Cell Line Km12 L4: High MetastaticPotential (derived 308731 from Km12C) 2 Human Colon Cell Line Km12C: LowMetastatic Potential 284771 3 Human Breast Cancer Cell Line MDA-MB-231:High Metastatic 326937 Potential; micro-metastases in lung 4 HumanBreast Cancer Cell Line MCF7: Non Metastatic 318979 8 Human Lung CancerCell Line MV-522: High Metastatic Potential 223620 9 Human Lung CancerCell Line UCP-3: Low Metastatic Potential 312503 12 Human microvascularendothelial cells (HMEC) - UNTREATED 41938 (PCR (OligodT) cDNA library)13 Human microvascular endothelial cells (HMEC) - bFGF TREATED 42100(PCR (OligodT) cDNA library) 14 Human microvascular endothelial cells(HMEC) - VEGF TREATED 42825 (PCR (OligodT) cDNA library) 15 NormalColon - UC#2 Patient (MICRODISSECTED PCR (OligodT) 282722 cDNA library)16 Colon Tumor - UC#2 Patient (MICRODISSECTED PCR (OligodT) 298831 cDNAlibrary) 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467(MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3Patient (MICRODISSECTED PCR (OligodT) 36216 cDNA library) 19 ColonTumor - UC#3 Patient (MICRODISSECTED PCR (OligodT) 41388 cDNA library)20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956(MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived fromnormal prostate epithelium 164801 22 WOca Cells derived from GleasonGrade 4 prostate cancer epithelium 162088 23 Normal Lung Epithelium ofPatient #1006 (MICRODISSECTED PCR 306198 (OligodT) cDNA library) 24Primary tumor, Large Cell Carcinoma of Patient #1006 309349(MICRODISSECTED PCR (OligodT) cDNA library)

The KM12L4 and KM12C cell lines are described in Example 41 above. TheMDA-MB-231 cell line was originally isolated from pleural effusions(Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastaticpotential, and forms poorly differentiated adenocarcinoma grade II innude mice consistent with breast carcinoma. The MCF7 cell line wasderived from a pleural effusion of a breast adenocarcinoma and isnon-metastatic. The MV-522 cell line is derived from a human lungcarcinoma and is of high metastatic potential. The UCP-3 cell line is alow metastatic human lung carcinoma cell line; the MV-522 is a highmetastatic variant of UCP-3. These cell lines are well-recognized in theart as models for the study of human breast and lung cancer (see, e.g.,Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7);Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ransonet al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al,Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al.,Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990)11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637;(MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); andZhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples oflibraries 15-20 are derived from two different patients (UC#2, andUC#3). The bFGF-treated HMEC were prepared by incubation with bFGF at 10ng/ml for 2 hrs; the VEGF-treated HMEC were prepared by incubation with20 ng/ml VEGF for 2 hrs. Following incubation with the respective growthfactor, the cells were washed and lysis buffer added for RNApreparation. The GRRpz and WOca cell lines were provided by Dr. Donna M.Peehl, Department of Medicine, Stanford University School of Medicine.GRRpz was derived from normal prostate epithelium. The WOca cell line isa Gleason Grade 4 cell line.

Each of the libraries is composed of a collection of cDNA clones that inturn are representative of the mRNAs expressed in the indicated mRNAsource. In order to facilitate the analysis of the millions of sequencesin each library, the sequences were assigned to clusters. The concept of“cluster of clones” is derived from a sorting/grouping of cDNA clonesbased on their hybridization pattern to a panel of roughly 300 7 bpoligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29).Random cDNA clones from a tissue library are hybridized at moderatestringency to 300 7 bp oligonucleotides. Each oligonucleotide has somemeasure of specific hybridization to that specific clone. Thecombination of 300 of these measures of hybridization for 300 probesequals the “hybridization signature” for a specific clone. Clones withsimilar sequence will have similar hybridization signatures. Bydeveloping a sorting/grouping algorithm to analyze these signatures,groups of clones in a library can be identified and brought togethercomputationally. These groups of clones are termed “clusters”. Dependingon the stringency of the selection in the algorithm (similar to thestringency of hybridization in a classic library cDNA screeningprotocol), the “purity” of each cluster can be controlled. For example,artifacts of clustering may occur in computational clustering just asartifacts can occur in “wet-lab” screening of a cDNA library with 400 bpcDNA fragments, at even the highest stringency. The stringency used inthe implementation of cluster herein provides groups of clones that arein general from the same cDNA or closely related cDNAs. Closely relatedclones can be a result of different length clones of the same cDNA,closely related clones from highly related gene families, or splicevariants of the same cDNA.

Differential expression for a selected cluster was assessed by firstdetermining the number of cDNA clones corresponding to the selectedcluster in the first library (Clones in 1^(st)), and the determining thenumber of cDNA clones corresponding to the selected cluster in thesecond library (Clones in 2^(nd)). Differential expression of theselected cluster in the first library relative to the second library isexpressed as a “ratio” of percent expression between the two libraries.In general, the “ratio” is calculated by: 1) calculating the percentexpression of the selected cluster in the first library by dividing thenumber of clones corresponding to a selected cluster in the firstlibrary by the total number of clones analyzed from the first library;2) calculating the percent expression of the selected cluster in thesecond library by dividing the number of clones corresponding to aselected cluster in a second library by the total number of clonesanalyzed from the second library; 3) dividing the calculated percentexpression from the first library by the calculated percent expressionfrom the second library. If the “number of clones” corresponding to aselected cluster in a library is zero, the value is set at 1 to aid incalculation. The formula used in calculating the ratio takes intoaccount the “depth” of each of the libraries being compared, i.e., thetotal number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentiallyexpressed between two samples when the ratio value is greater than atleast about 2, preferably greater than at least about 3, more preferablygreater than at least about 5, where the ratio value is calculated usingthe method described above. The significance of differential expressionis determined using a z score test (Zar, Biostatistical Analysis,Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298(1974).

Using the methods and libraries described above, 37 of the isolatedpolynucleotides were identified as being differentially expressed acrossmultiple libraries. Table 65 provides a list of these polynucleotidesand their corresponding sequence names. The sequences of each of theabove-referenced polynucleotides were determined using methods wellknown in the art. The sequences of the 37 polynucleotides, assigned SEQID NOS:8804-8840, are provided in the Sequence Listing below. TABLE 65Polynucleotides corresponding to differentially expressed genes SEQ IDNO. Sequence Name 8804 13905 8805 RTA00000281F.o.21.1 8806RTA00000348R.d.10.1 8807 RTA00000177AF.d.22.3 8808 RTA00000684F.e.07.18809 RTA00000618F.p.24.1 8810 RTA00000596F.d.12.1 8811RTA00000421F.d.20.1 8812 17090 8813 RTA00000161A.1.7.1 8814RTA00000155A.k.14.1 8815 RTA00000163A.e.10.1 8816 RTA00000126A.o.15.28817  2546 8818 RTA00000144A.p.8.1 8819 RTA00000618F.k.16.1 8820RTA00000742F.o.19.1 8821 RTA00000148A.o.18.1 8822 RTA00000619F.d.02.18823 RTA00000683F.1.19.1 8824 RTA00000172A.d.9.3 8825RTA00000165A.d.16.1 8826 RTA00000188AR.d.05.1 8827 RTA00000183AF.n.14.18828 RTA00000346F.g.11.1 8829 RTA00000183AR.n.14.1 8830RTA00000742F.g.08.1 8831 RTA00000689F.h.06.1 8832 RTA00000185AF.b.9.18833 RTA0000018SAF.b.9.2 8834 RTA00000192AR.o.8.2 8835RTA00000192AF.o.8.1 8836 RTA00000685F.j.16.1 8837 RTA00000621F.i.13.28838 RTA00000685F.1.23.1 8839 16405 8840 028035AThe differential expression data for these sequences is provided below.

Example 43 Genes Differentially Expressed Genes in Non-Metastatic or LowMetastatic Potential Cancer Cells Versus High Metastatic PotentialCancer Cells

The relative levels of expression of genes corresponding to SEQ IDNO:8804-8840 across various libraries described in Table 64 aresummarized in Table 66 below. TABLE 66 Genes Differentially ExpressedAcross Multiple Library Comparisons SEQ ID NO: Cell or Tissue Sample andCancer State Compared RATIO 8804 Low Met Breast (lib4) > High Met Breast(lib3) 5.38 8804 Low Met Colon (lib2) > High Met Colon (lib1) 6.14 8805Low Met Colon (lib2) > High Met Colon (lib1) 3.56 8805 Low Met Breast(lib4) > High Met Breast (lib3) 2.73 8805 Normal Prostate (lib21) >Prostate Cancer (lib 22) 4.92 8806 Low Met Colon (lib2) > High Met Colon(lib1) 3.52 8806 Low Met Breast (lib4) > High Met Breast (lib3) 4.3 8807Low Met Colon (lib2) > High Met Colon (lib1) 3.52 8807 Low Met Breast(lib4) > High Met Breast (lib3) 4.3 8808 High Met Lung (lib8) > Low MetLung (lib9) 3.35 8808 Low Met Colon (lib2) > High Met Colon (lib1) 3.478808 Low Met Breast (lib4) > High Met Breast (lib3) 30.24 8809 Low MetBreast (lib4) > High Met Breast (lib3) 30.24 8809 Low Met Colon (lib2) >High Met Colon (lib1) 3.47 8809 High Met Lung (lib8) > Low Met Lung(lib9) 3.35 8810 Low Met Colon (lib2) > High Met Colon (lib1) 3.47 8810Low Met Breast (lib4) > High Met Breast (lib3) 30.24 8810 High Met Lung(lib8) > Low Met Lung (lib9) 3.35 8811 Low Met Breast (lib4) > High MetBreast (lib3) 2.42 8811 Low Met Colon (lib2) > High Met Colon (lib1)2.63 8812 Low Met Colon (lib2) > High Met Colon (lib1) 2.49 8812 Low MetBreast (lib4) > High Met Breast (lib3) 2.19 8812 Low Met Lung (lib9) >High Met Lung (lib8) 3.07 8813 Low Met Breast (lib4) > High Met Breast(lib3) 41 8813 High Met Lung (lib8) > Low Met Lung (lib9) 2.29 8814 LowMet Breast (lib4) > High Met Breast (lib3) 7.35 8814 Normal Prostate(lib21) > Prostate Cancer (lib 22) 9.84 8815 High Met Breast (lib3) >Low Met Breast (lib4) 6.41 8815 High Met Colon (lib1) > Low Met Colon(lib2) 2.39 8816 High Met Colon (lib1) > Low Met Colon (lib2) 2.05 8816High Met Breast (lib3) > Low Met Breast (lib4) 9.76 8817 Low Met Breast(lib4) > High Met Breast (lib3) 4.54 8817 High Met Lung (lib8) > Low MetLung (lib9) 10.48 8817 Low Met Colon (lib2) > High Met Colon (lib1) 8.318818 Low Met Breast (lib4) > High Met Breast (lib3) 2.05 8818 Low MetColon (lib2) > High Met Colon (lib1) 7.05 8819 Low Met Colon (lib2) >High Met Colon (lib1) 4.34 8819 Low Met Breast (lib4) > High Met Breast(lib3) 6.75 8820 Low Met Colon (lib2) > High Met Colon (lib1) 4.34 8820Low Met Breast (lib4) > High Met Breast (lib3) 6.75 8821 Low Met Colon(lib2) > High Met Colon (lib1) 3.98 8821 Low Met Breast (lib4) > HighMet Breast (lib3) 3.31 8821 Low Met Lung (lib9) > High Met Lung (lib8)2.5 8822 Low Met Colon (lib2) > High Met Colon (lib1) 3.56 8822 NormalProstate (lib21) > Prostate Cancer (lib 22) 4.92 8822 Low Met Breast(lib4) > High Met Breast (lib3) 2.73 8823 Normal Prostate (lib21) >Prostate Cancer (lib 22) 4.92 8823 Low Met Breast (lib4) > High MetBreast (lib3) 2.73 8823 Low Met Colon (lib2) > High Met Colon (lib1)3.56 8824 Low Met Colon (lib2) > High Met Colon (lib1) 3.56 8824 Low MetBreast (lib4) > High Met Breast (lib3) 2.73 8824 Normal Prostate(lib21) > Prostate Cancer (lib 22) 4.92 8825 Low Met Colon (lib2) > HighMet Colon (lib1) 3.52 8825 Low Met Breast (lib4) > High Met Breast(lib3) 3.55 8825 High Met Lung (lib8) > Low Met Lung (lib9) 17.7 8826Low Met Colon (lib2) > High Met Colon (lib1) 3.25 8826 Low Met Breast(lib4) > High Met Breast (lib3) 3.07 8827 Low Met Breast (lib4) > HighMet Breast (lib3) 3.07 8827 Low Met Colon (lib2) > High Met Colon (lib1)3.25 8828 Low Met Colon (lib2) > High Met Colon (lib1) 3.25 8828 Low MetBreast (lib4) > High Met Breast (lib3) 3.07 8829 Low Met Colon (lib2) >High Met Colon (lib1) 3.25 8829 Low Met Breast (lib4) > High Met Breast(lib3) 3.07 8830 Low Met Colon (lib2) > High Met Colon (lib1) 3.25 8830Low Met Breast (lib4) > High Met Breast (lib3) 3.07 8831 Low Met Colon(lib2) > High Met Colon (lib1) 2.86 8831 Low Met Breast (lib4) > HighMet Breast (lib3) 8.14 8832 Low Met Colon (lib2) > High Met Colon (lib1)2.1 8832 Low Met Breast (lib4) > High Met Breast (lib3) 2.5 8833 Low MetColon (lib2) > High Met Colon (lib1) 2.1 8833 Low Met Breast (lib4) >High Met Breast (lib3) 2.5 8834 Low Met Colon (lib2) > High Met Colon(lib1) 2.1 8834 Low Met Breast (lib4) > High Met Breast (lib3) 2.5 8835Low Met Colon (lib2) > High Met Colon (lib1) 2.1 8835 Low Met Breast(lib4) > High Met Breast (lib3) 2.5 8836 Low Met Colon (lib2) > High MetColon (lib1) 2.14 8836 Low Met Breast (lib4) > High Met Breast (lib3)2.27 8837 Normal Prostate (lib21) > Prostate Cancer (lib 22) 5.9 8837Low Met Colon (lib2) > High Met Colon (lib1) 2.1 8837 Low Met Breast(lib4) > High Met Breast (lib3) 2.18 8838 Normal Prostate (lib21) >Prostate Cancer (lib 22) 5.9 8838 Low Met Colon (lib2) > High Met Colon(lib1) 2.1 8838 Low Met Breast (lib4) > High Met Breast (lib3) 2.18 8839Low Met Colon (lib2) > High Met Colon (lib1) 2.1 8839 Low Met Breast(lib4) > High Met Breast (lib3) 2.18 8839 Normal Prostate (lib21) >Prostate Cancer (lib 22) 5.9 8840 Low Met Colon (lib2) > High Met Colon(lib1) 2.17 8840 Low Met Breast (lib4) > High Met Breast (lib3) 2.9 8840Low Met Lung (lib9) > High Met Lung (lib8) 3.4Key for Table 66:High Met = high metastatic potential;Low Met = low metastatic potential;met = metastasized;tumor = non-metastasized tumor

The relative expression levels of the genes corresponding to thepolynucleotides above can be exploited in diagnostic and prognosticassays. For example, where the polynucleotide corresponds to a gene thatis expressed at a relatively higher level in a low metastatic potentialcell relative to a high metastatic potential cell (or at a relativelyhigher level in normal cells or nonmetastasized tumor cells relativelyto metastatic or high metastatic potential cancerous cells), expressionof the gene can serve as a marker indicating low risk of metastasis andmay encode a suppressor of metastasis. Where the polynucleotidecorresponds to a gene expressed at a relatively higher level in a highmetastatic potential cell relative to a low metastatic potential cell,expression of the gene can serve as a marker of metastatic potential,indicating the need for more aggressive therapy.

Example 44 Identification of a Gene and Protein Encoded by thePolynucleotide

SEQ ID NOS:8804-8840 were translated in all three reading frames, andthe nucleotide sequences and translated amino acid sequences used asquery sequences to search for homologous sequences in either the GenBank(nucleotide sequences) or Non-Redundant Protein (amino acid sequences)databases. Query and individual sequences were aligned using the BLAST2.0 programs, available at the world wide web of the NCBI. (see alsoAltschul, et al. Nucleic Acids Res. (1997) 25:3389-3402). The sequenceswere masked to various extents to prevent searching of repetitivesequences or poly-A sequences, using the XBLAST program for masking lowcomplexity.

The results are provided in Table 67 below. TABLE 67 Results of searchof publicly available sequence databases using SEQ ID NOS: 8804-8840 asquery sequences SEQ ID NO: Description 8804 yt88d06.r1 Homo sapiens cDNAclone 231371 5′. (EST Accession No. H56522) 8805 za04c10.r1 Soaresmelanocyte 2NbHM Homo sapiens cDNA clone 291570 5′ (EST Accession No.W03386) 8806 Homo sapiens heat shock factor binding protein 1 HSBP1mRNA, complete cds (GenBank Accession No. AF068754) 8807 Homo sapiensheat shock factor binding protein 1 HSBP1 mRNA, complete cds (GenBankAccession No. AF068754) 8808 Homo sapiens CGI-122 protein mRNA, completecds (GenBank Accession No. AF151880.1) 8809 Homo sapiens CGI-122 proteinmRNA, complete cds (GenBank Accession No. AF151880.1) 8810 Homo sapiensCGI-122 protein mRNA, complete cds (GenBank Accession No. AF151880.1)8811 zn42b05.s1 Stratagene endothelial cell 937223 Homo sapiens cDNAclone 550065 3′ similar to SW: RPC9_YEAST P28000 DNA-DIRECTED RNAPOLYMERASES I AND III 16 KD POLYPEPTIDE (EST Accession No. AA102570)8812 yv31g09.r1 Soares fetal liver spleen 1NFLS Homo sapiens cDNA clone244384 5′ similar to contains Alu repetitive element (EST Accession No.N72329) 8813 tz22h11.x1 NCI_CGAP_Ut2 Homo sapiens cDNA clone IMAGE:2289381 3′, mRNA sequence (EST Accession No. AI635233.1) 8814 zi02h12.r1Soares fetal liver spleen 1NFLS S1 Homo sapines cDNA clone 429671 5′similar to contains Alu repetitive element (EST Accession No. AA011438)8815 Human quiescin (Q6) mRNA 8816 Human Treacher Collins Syndrome 8817Human mRNA for annexin IV (carbohydrate-binding protein p33/41) 8818Human mRNA for TGIF protein 8819 Human MHC class I lymphocyte antigen(HLA-E) (HLA-6.2) 8820 Human HLA-E class I mRNA 8821 Human Mpv17 mRNA8822 Human kidney cyclophilin C 8823 Human kidney cyclophilin C 8824Human kidney cyclophilin C 8825 Human mRNA for 26S proteasome subunitp55 8826 Human gamma-interferon-inducible protein (IP-30) mRNA 8827Human gamma-interferon-inducible protein (IP-30) mRNA 8828 Humangamma-interferon-inducible protein (IP-30) mRNA 8829 Humangamma-interferon-inducible protein (IP-30) mRNA 8830 Humangamma-interferon-inducible protein (IP-30) mRNA 8831 Human Na+/H+exchange regulatory co-factor (NHERF) mRNA 8832 Human mRNA formitochondrial dodecenoyl-CoA delta-isomerase 8833 Human mRNA formitochondrial dodecenoyl-CoA delta-isomerase 8834 Human mRNA formitochondrial dodecenoyl-CoA delta-isomerase 8835 Human mRNA formitochondrial dodecenoyl-CoA delta-isomerase 8836 Human (clone PSK-J3)cyclin-dependent protein kinase mRNA 8837 Human serinehydroxymethyltransferase mRNA 8838 Human serine hydroxymethyltransferasemRNA 8839 Human serine hydroxymethyltransferase mRNA 8840 Human DNAdamage-inducible RNA binding protein (A18hnRNP).Key:ES = EST database;GB = GenBank database

SEQ ID NO:8804 corresponds to a cDNA clone generated from an ESTisolated from human pineal gland (Hillier et al. Genome Res. (1996)6(9):807-28).

SEQ ID NO:8805 corresponds to a sequence contained within a cDNA clonederived from an EST isolated from a human melanocyte 2NbHM.

SEQ ID NOS:8806 and 8807 correspond to a sequence encoding a human heatchock factor binding protein, HSBP-1, which acts as a negative regulatorof the heat shock response through its interaction with heat shockfactor 1 (HSF1) (Satyal et al. Genes Dev. (1998) 12(13):1962-74).Briefly, HSF-1 responds to stress by undergoing conformationaltransition from an inert non-DNA binding monomer to an active trimedthat exhibits rapid DNA binding and activity as a transcriptionalactivator. Attenuation of the inducible transcriptional response, whichoccurs during heat shock or upon recovery at non-stress conditions,involves dissociation of the HSF1 trimer and loss of activity. HSBP-1, anuclear-localized, conserved, 76-amino-acid protein, contains twoextended arrays of hydrophobic repeats that interact with HSF-1 heptadrepeats of the active trimeric state of HSF1. During attenuation of HSF1to the inert monomer, HSBP1 also associates with Hsp70. Through itsinteraction with HSF-1, HSBP1 negatively affects HSF-1 DNA-bindingactivity.

SEQ ID NOS:8808-8810 correspond to a gene encoding human CGI-122protein.

SEQ ID NO:8811 corresponds to a cDNA clone generated from an ESTisolated from human endothelial cells (Hillier et al. Genome Res. (1996)6(9):807-28).

SEQ ID NOS:8812 and 8814 correspond to a cDNA clone generated from anEST isolated human fetal liver and spleen (Hillier et al. Genome Res.(1996) 6(9):807-28).

SEQ ID NO:8813 corresponds to a sequence contained within a human cDNAclone isolated from moderately-differentiated endometrialadenocarcinoma.

The gene corresponding to SEQ ID NO:8816 encodes human quiescin Q6(Coppoch et al., 1998, Proc. Amer. Assoc. Can. Res. 39:471).

The gene corresponding to SEQ ID NO:8817 encodes a human TreacherCollins Syndrome protein. Treacher Collins Syndrome (TCS) is anautosomal dominant disorder of craniofacial development includinghearing loss and cleft palate. The TCS gene (called Treacle) has beenpositionally cloned and has 26 exons exhibiting a low complexityserine/alanine-rich protein of about 144 kDa (Dixon et al., 1997, GenomeRes. 7:223-234). Thirty-five mutations in the gene are reported fromstudies of individuals and families affected by Treacher CollinsSyndrome (Edwards et al., 1997, Am. J. Human Genet. 60:515-524. Mutationin Treacle generally results in premature termination of the predictedprotein (Nat. Genet. 12:130-136, 1996).

The gene corresponding to SEQ ID NO: 8817 encodes human annexin IV(carbohydrate-binding protein p33/41). Annexins are a family of Ca2+ andphospholipid binding proteins. Annexin IV binds to glycosaminoglycans(GAGs) in a calcium-dependent manner (Kojima et al., 1996, J. Biol.Chem. 271:7679-7685; Ishitsuka et al., 1998, J. Biol. Chem.273:9935-9941; and Satoh et al., 1997, Biol. Pharm. Bull. 20:224-229).Annexin IV is highly expressed in various human adenocarcinoma celllines (Satoh et al., 1997, FEBS Lett. 405:107-110), and calcium-inducedrelocation of annexin IV is observed in a human osteosarcoma cell line(Mohiti et al., 1995, Mol. Membr. Biol. 12:321-329).

The gene corresponding to SEQ ID NO: 8818 encodes human TGIF protein(Bertolino et al., 1995, J. Biol. Chem. 270:31178-31188).

The gene corresponding to SEQ ID NO:8819 encodes human MHC Class Ilymphocyte antigen (HLA-E) (HLA-6.2), as described by Koller et al.,1988, J. Immunol. 141:897-904.

The gene corresponding to SEQ ID NO:8820 encodes human HLA-E class ImRNA, as described by Mizuno et al., 1988, J. Immunol. 140:4024-4030.

The gene corresponding to SEQ ID NO:8821 is the human glomerulosclerosisgene Mpv17, as described by Karasawa, 1993, Hum. Mol. Genet.11:1829-1834.

The gene corresponding to any one or more of SEQ ID NOS:8822-8824encodes a human cyclophilin C (Schneider et al., 1994, Biochemistry33:8218-8224).

The gene corresponding to SEQ ID NO:8825 encodes human 265 proteasomesubunit p55. Human 26S proteasome is a heterodimer of p44.5 and p55(Saito et al., 1997, Gene 203:241-250) and plays a major role in thenon-lysosomal degradation of intracellular proteins (Mason et al., 1998,FEBS Lett. 430:269-274). Homologues of 26S proteasome subunits areregulators of transcription and translation as described in Aravind andPonting, 1998, Protein Sci. 7:1250-1254. Proteasomes are cylindricalparticles made up of a stack of four heptameric rings (Rivett et al.,1997, Mol. Biol. Rep. 24:99-102) and 26S proteasome has stringentorganization of ATPases, as described in Seeger et al., 1997, Mol. Biol.Rep. 24:83-88. In mammalian cells, the proteasome is a site fordegradation of proteins, as described in Goldberg et al., 1997, Biol.Chem. 378:131-140. In addition, proteolytic processing involving 26Sproteasome occurs in lesions of Alzheimer's Disease and dementia withLewy bodies (Fergusson et al., 1996, Neurosci. Lett. 219:167-170).

The gene corresponding to any one or more of SEQ ID NOS:8826-8830encodes human gamma-interferon-inducible protein (IP-30), Luster et al.,1988, J. Biol. Chem. 263:12036-12043.

The gene corresponding to SEQ ID NO:8831 encodes human Na⁺/H⁺ exchangeregulatory co-factor (NHEFR) (Murphy et al., 1998, J. Biol. Chem. inpress).

The gene corresponding to any one or more of SEQ ID NOS:8832-8835encodes human mitochondrial dodecenoyl-CoA delta-isomerase.

The gene corresponding to SEQ ID NO:8836 encodes human (clone PSK-J3)cyclin-dependent protein kinase (Hanks, 1987, Proc. Natl. Acad. Sci.84:388-392).

The gene corresponding to any one or more of SEQ ID NOS:8837-8839encodes human serine hydroxymethyltransferase. Human serinehydroxymethyltransferase is a pyridoxine enzyme that is low in restinglymphocytes but increases upon antigenic or mitogenic stimuli, such asin an immune response (Trakatellis et al., 1997, Postgrad. Med. J.73:617-622, and Trakatellis et al., 1994, Postgrad. Med. J. 70(Suppl1):S89-S92). The catalytic function of the protein is tested asdescribed in Kim et al., 1997, Anal. Biochem. 253:201-209.

The polynucleotide comprising SEQ ID NO:8840 corresponds to a GenBankentry having accession number AF021336, an mRNA complete coding sequencefor human DNA damage-inducible RNA binding protein (A18hnRNP). The pvalue of 1.9⁻¹¹³ indicates an extremely high level of similarity betweenthe sequence of SEQ ID NO: 8840 and the identified GenBank sequence.Likewise, the protein search identified a high level of similarity (pvalue of 2.4⁻⁶³) between the amino acid translated from the secondreading frame of the polynucleotide of SEQ ID NO: 8840 and the entryHUMCIRPA_(—)1 for human mRNA for glycine-rich RNA binding proteincold-inducible RNA-binding protein (CIRP). The search of DBESTidentified accession number AA166551, murine CIRP, with a p value of5.8⁻¹¹⁵. CIRP is an 18 kD protein induced in mouse cells by mild coldstress and consists of an N-terminal RNA-binding domain and a C-terminalglycine-rich domain (Nishiyama et al., 1997, J. Cell Biol. 137(4):899).Lowering the culture temperature of BALB/3T3 cells from 37° C. to 32° C.induces CIRP expression and impairs cell growth. Suppression of CIRPwith antisense oligonucleotides alleviates the impaired growth, whileoverexpression of CIRP impairs growth at 37° C. and prolongs the G1phase of the cell cycle (Nishiyama et al., supra). The cloning andcharacterization of human CIRP was described by Nishiyama et al., 1997,Gene 204(1-2):115).

Deposit Information. The materials described in Table 68 were depositedwith the American Type Culture Collection (CMCC=Chiron Master CultureCollection). TABLE 68 Cell Lines Deposited with ATCC CMCC Cell LineDeposit Date ATCC Accession No. Accession No. KM12L4-A Mar. 19, 1998CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15,1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377

The deposits described herein are provided merely as convenience tothose of skill in the art, and is not an admission that a deposit isrequired under 35 U.S.C. §112. The sequence of the polynucleotidescontained within the deposited material, as well as the amino acidsequence of the polypeptides encoded thereby, are incorporated herein byreference and are controlling in the event of any conflict with thewritten description of sequences herein. A license may be required tomake, use, or sell the deposited material, and no such license isgranted hereby

Example 45 Source of Biological Materials and Overview of NovelPolynucleotides Expressed by the Biological Materials

cDNA libraries were constructed from either human colon cancer cell lineKm12L4-A (Morikawa, et al., Cancer Research (1988) 48:6863), KM12C(Morikawa et al. Cancer Res. (1988)48:1943-1948), or MDA-MB-231(Brinkley et al. Cancer Res. (1980) 40:3118-3129) was used to constructa cDNA library from mRNA isolated from the cells. Sequences expressed bythese cell lines were isolated and analyzed; most sequences were about275-300 nucleotides in length. The KM12L4-A cell line is derived fromthe KM12C cell line. The KM12C cell line, which is poorly metastatic(low metastatic) was established in culture from a Dukes' stage B₂surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). TheKML4-A is a highly metastatic subline derived from KM12C (Yeatman et al.Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am.Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived celllines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as amodel cell line for the study of colon cancer (see, e.g., Moriakawa etal., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman etal., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246).The MDA-MB-231 cell line was originally isolated from pleural effusions(Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastaticpotential, and forms poorly differentiated adenocarcinoma grade II innude mice consistent with breast carcinoma.

The sequences of the isolated polynucleotides were first masked toeliminate low complexity sequences using the XBLAST masking program(Claverie “Effective Large-Scale Sequence Similarity Searches,” In:Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed.,Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); seeparticularly Claverie, in “Automated DNA Sequencing and AnalysisTechniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, SanDiego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally,masking does not influence the final search results, except to eliminatesequences of relative little interest due to their low complexity, andto eliminate multiple “hits” based on similarity to repetitive regionscommon to multiple sequences, e.g., Alu repeats. Masking resulted in theelimination of 43 sequences. The remaining sequences were then used in aBLASTN vs. GenBank search; sequences that exhibited greater than 70%overlap, 99% identity, and a p value of less than 1×10⁻⁴⁰ werediscarded. Sequences from this search also were discarded if theinclusive parameters were met, but the sequence was ribosomal orvector-derived.

The resulting sequences from the previous search were classified intothree groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP(non-redundant proteins) database search: (1) unknown (no hits in theGenBank search), (2) weak similarity (greater than 45% identity and pvalue of less than 1×10⁻⁵), and (3) high similarity (greater than 60%overlap, greater than 80% identity, and p value less than 1×10⁻⁵).Sequences having greater than 70% overlap, greater than 99% identity,and p value of less than 1×10⁻⁴⁰ were discarded.

The remaining sequences were classified as unknown (no hits), weaksimilarity, and high similarity (parameters as above). Two searches wereperformed on these sequences. First, a BLAST vs. EST database search wasperformed and sequences with greater than 99% overlap, greater than 99%similarity and a p value of less than 1×10⁻⁴⁰ were discarded. Sequenceswith a p value of less than 1×10⁻⁶⁵ when compared to a database sequenceof human origin were also excluded. Second, a BLASTN vs. Patent GeneSeqdatabase was performed and sequences having greater than 99% identity, pvalue less than 1×10⁻⁴⁰, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rulesand redundancies in the dataset. Sequences with a p value of less than1×10⁻¹¹¹ in relation to a database sequence of human origin werespecifically excluded. The final result provided the 982 sequenceslisted as SEQ ID NOS:8841-9785 in the accompanying Sequence Listing andsummarized in Table 69A (inserted prior to claims). Each identifiedpolynucleotide represents sequence from at least a partial mRNAtranscript.

Table 69A provides: 1) the SEQ ID NO assigned to each sequence for usein the present specification; 2) the filing date of the U.S. priorityapplication in which the sequence was first filed; 3) the attorneydocket number assigned to the priority application (for internal use);4) the SEQ ID NO assigned to the sequence in the priority application;5) the sequence name used as an internal identifier of the sequence; and6) the name assigned to the clone from which the sequence was isolated.Because the provided polynucleotides represent partial mRNA transcripts,two or more polynucleotides of the invention may represent differentregions of the same mRNA transcript and the same gene. Thus, if two ormore SEQ ID NOS: are identified as belonging to the same clone, theneither sequence can be used to obtain the full-length mRNA or gene.

In order to confirm the sequences of SEQ ID NOS: 8841-9785, the cloneswere retrieved from a library using a robotic retrieval system, and theinserts of the retrieved clones re-sequenced. These “validation”sequences are provided as SEQ ID 9786:983-9799 in the Sequence Listing,and a summary of the “validation” sequences provided in Table 69B(inserted prior to claims). Table 69B provides: 1) the SEQ ID NOassigned to each sequence for use in the present specification; 2) thesample name assigned to the “validation”sequence obtained; and 3) thename of the clone that contains the indicated “validation”sequence.“Validation” sequences can be correlated with the original sequencesthey validate by referring to Table 69A. Because the “validation”sequences are often longer than the original polynucleotide sequencesand thus provide additional sequence information. All validationsequences can be obtained either from the corresponding clone or from acDNA library described herein (e.g., using primers designed from thesequence provided in the sequence listing). TABLE 69A Priority ApplnInformation SEQ ID SEQ ID NO: Filed Dkt NO. NO: Sequence Name Clone Name8841 Sep. 28, 1998 1492.001 1 RTA00000617F.o.18.2 M00005513A:H01 8842Sep. 28, 1998 1492.001 2 RTA00001075F.h.12.1 M00005434A:F11 8843 Sep.28, 1998 1492.001 3 RTA00001076F.m.09.1 M00006946B:C08 8844 Sep. 28,1998 1492.001 4 RTA00001075F.o.08.1 M00005628D:A10 8845 Sep. 28, 19981492.001 5 RTA00001064F.f.14.1 M00005465A:A07 8846 Sep. 28, 19981492.001 6 RTA00001075F.n.19.1 M00005614A:B07 8847 Sep. 28, 19981492.001 7 RTA00001075F.i.24.1 M00005453B:B06 8848 Sep. 28, 19981492.001 8 RTA00001075F.p.24.1 M00005721D:B03 8849 Sep. 28, 19981492.001 9 RTA00001075F.o.04.1 M00005621B:C09 8850 Sep. 28, 19981492.001 10 RTA00000616F.j.04.1 M00005412D:G07 8851 Sep. 28, 19981492.001 11 RTA00001064F.k.01.1 M00005708C:D11 8852 Sep. 28, 19981492.001 12 RTA00001064F.j.19.1 M00005657B:F11 8853 Sep. 28, 19981492.001 13 RTA00001065F.a.22.1 M00006920B:H07 8854 Sep. 28, 19981492.001 14 RTA00001076F.d.11.1 M00006623C:G07 8855 Sep. 28, 19981492.001 15 RTA00000615F.e.08.2 M00004872A:D07 8856 Sep. 28, 19981492.001 16 RTA00000617F.p.05.2 M00005515D:G02 8857 Sep. 28, 19981492.001 17 RTA00001076F.f.03.1 M00006668D:B10 8858 Sep. 28, 19981492.001 18 RTA00001064F.l.17.2 M00006582A:F12 8859 Sep. 28, 19981492.001 19 RTA00001076F.h.13.1 M00006745B:C05 8860 Sep. 28, 19981492.001 20 RTA00001075F.k.12.1 M00005482A:D08 8861 Sep. 28, 19981492.001 21 RTA00001076F.c.09.1 M00006594B:D05 8862 Sep. 28, 19981492.001 22 RTA00001076F.l.16.1 M00006919A:H12 8863 Sep. 28, 19981492.001 23 RTA00001076F.b.13.1 M00005825A:A10 8864 Sep. 28, 19981492.001 24 RTA00001065F.d.06.2 M00007078B:H04 8865 Sep. 28, 19981492.001 25 RTA00001075F.p.23.1 M00005721C:A12 8866 Sep. 28, 19981492.001 26 RTA00001075F.n.22.1 M00005616B:E11 8867 Sep. 28, 19981492.001 27 RTA00001075F.o.21.1 M00005648C:E10 8868 Sep. 28, 19981492.001 28 RTA00001065F.b.22.1 M00006968A:H05 8869 Sep. 28, 19981492.001 29 RTA00001075F.p.06.1 M00005698A:F12 8870 Sep. 28, 19981492.001 30 RTA00001076F.d.19.1 M00006630A:E05 8871 Sep. 28, 19981492.001 31 RTA00001075F.e.14.1 M00005375B:H03 8872 Sep. 28, 19981492.001 32 RTA00001065F.f.02.1 M00007186A:A12 8873 Sep. 28, 19981492.001 33 RTA00001064F.p.03.1 M00006814D:D09 8874 Sep. 28, 19981492.001 34 RTA00001076F.i.19.1 M00006813B:E04 8875 Sep. 28, 19981492.001 35 RTA00001077F.c.06.1 M00007157B:B04 8876 Sep. 28, 19981492.001 36 RTA00001064F.c.21.1 M00005366D:E12 8877 Sep. 28, 19981492.001 37 RTA00001065F.e.21.1 M00007177A:G07 8878 Sep. 28, 19981492.001 38 RTA00001076F.o.14.1 M00007038D:D01 8879 Sep. 28, 19981492.091 39 RTA00001064F.c.01.1 M00005327C:G08 8880 Sep. 28, 19981492.001 40 RTA00001064F.d.16.1 M00005397A:G08 8881 Sep. 28, 19981492.001 41 RTA00000615F.e.05.2 M00004870D:E05 8882 Sep. 28, 19981492.001 42 RTA00000616F.j.12.1 M00005413D:G12 8883 Sep. 28, 19981492.001 43 RTA00001075F.a.17.1 M00004852B:H08 8884 Sep. 28, 19981492.001 44 RTA00001076F.n.10.1 M00006989C:B01 8885 Sep. 28, 19981492.001 45 RTA00001075F.l.04.1 M00005505D:H08 8886 Sep. 28, 19981492.001 46 RTA00001075F.l.10.1 M00005509B:E10 8887 Sep. 28, 19981492.001 47 RTA00001075F.i.09.1 M00005444D:D01 8888 Sep. 28, 19981492.001 48 RTA00001075F.j.13.1 M00005464B:B08 8889 Sep. 28, 19981492.001 49 RTA00001076F.e.03.1 M00006635A:C01 8890 Sep. 28, 19981492.001 50 RTA00001076F.j.14.1 M00006837B:H12 8891 Sep. 28, 19981492.001 51 RTA00001075F.g.19.1 M00005418C:B09 8892 Sep. 28, 19981492.001 52 RTA0000I075F.m.05.1 M00005538C:H11 8893 Sep. 28, 19981492.001 53 RTA00001076F.p.03.1 M00007046D:E10 8894 Sep. 28, 19981492.001 54 RTA00001075F.h.19.1 M00005435B:F01 8895 Sep. 28, 19981492.001 55 RTA00001075F.h.14.1 M00005434C:E02 8896 Sep. 28, 19981492.001 56 RTA00001076F.l.14.1 M00006917B:C05 8897 Sep. 28, 19981492.001 57 RTA00001075F.h.17.1 M00005434D:H02 8898 Sep. 28, 19981492.001 58 RTA00001075F.f.18.1 M00005396C:H04 8899 Sep. 28, 19981492.001 59 RTA00001076F.l.03.1 M00006894D:A07 8900 Sep. 28, 19981492.001 60 RTA00001065F.d.07.2 M00007079D:H01 8901 Sep. 28, 19981492.001 61 RTA00001075F.e.18.1 M00005377C:F07 8902 Sep. 28, 19981492.001 62 RTA00001065F.d.03.2 M00007065D:A03 8903 Sep. 28, 19981492.001 63 RTA00001076F.b.18.1 M00006577A:B01 8904 Sep. 28, 19981492.001 64 RTA00001075F.m.16.1 M00005569B:E04 8905 Sep. 28, 19981492.001 65 RTA00001076F.d.13.1 M00006627C:C02 8906 Sep. 28, 19981492.001 66 RTA00001076F.i.16.1 M00006805D:H12 8907 Sep. 28, 19981492.001 67 RTA00001076F.p.10.1 M00007064B:E09 8908 Sep. 28, 19981492.001 68 RTA00001064F.p.14.1 M00006835D:C08 8909 Sep. 28, 19981492.001 69 RTA00001077F.b.04.1 M00007126D:H01 8910 Sep. 28, 19981492.001 70 RTA00001076F.d.04.1 M00006619A:G11 8911 Sep. 28, 19981492.001 71 RTA00001077F.a.22.1 M00007121D:A11 8912 Sep. 28, 19981492.001 72 RTA00001077F.c.19.1 M00007178D:A10 8913 Sep. 28, 19981492.001 73 RTA00001065F.f.06.1 M00007197D:D12 8914 Sep. 28, 19981492.001 74 RTA00000616F.f.11.3 M00005395D:D11 8915 Sep. 28, 19981492.001 75 RTA00001064F.l.13.2 M00006577B:F01 8916 Sep. 28, 19981492.001 76 RTA00001064F.o.08.1 M00006757D:H04 8917 Sep. 28, 19981492.001 77 RTA00001075F.o.03.1 M00005621A:B05 8918 Sep. 28, 19981492.001 78 RTA00001064F.l.23.2 M00006596D:H02 8919 Sep. 28, 19981492.001 79 RTA00001076F.e.01.1 M00006631D:G09 8920 Sep. 28, 19981492.001 80 RTA00001075F.j.22.1 M00005473C:F02 8921 Sep. 28, 19981492.001 81 RTA00001076F.h.16.1 M00006757A:C09 8922 Sep. 28, 19981492.001 82 RTA00001075F.j.08.1 M00005459B:A01 8923 Sep. 28, 19981492.001 83 RTA00001064F.o.19.1 M00006795C:B12 8924 Sep. 28, 19981492.001 84 RTA00001064F.o.07.1 M00006756D:G07 8925 Sep. 28, 19981492.001 85 RTA00001076F.i.09.1 M00006790D:F10 8926 Sep. 28, 19981492.001 86 RTA00001076F.i.22.1 M00006815D:D11 8927 Sep. 28, 19981492.001 87 RTA00001076F.c.21.1 M00006613C:C02 8928 Sep. 28, 19981492.001 88 RTA00001076F.j.19.1 M00006846A:B03 8929 Sep. 28, 19981492.001 89 RTA00001064F.o.13.1 M00006779D:F03 8930 Sep. 28, 19981492.001 90 RTA00001077F.a.06.1 M00007101C:H01 8931 Sep. 28, 19981492.001 91 RTA00001064F.n.01.1 M00006664A:C05 8932 Sep. 28, 19981492.001 92 RTA00001064F.c.12.1 M00005358A:H03 8933 Sep. 28, 19981492.001 93 RTA00001077F.d.07.1 M00007196D:D02 8934 Sep. 28, 19981492.001 94 RTA00001077F.c.18.1 M00007177B:C02 8935 Sep. 28, 19981492.001 95 RTA00001064F.g.12.1 M00005490B:B02 8936 Sep. 28, 19981492.001 96 RTA00001075F.b.07.1 M00004866C:H08 8937 Sep. 28, 19981492.001 97 RTA00000617F.p.03.2 M00005515B:B08 8938 Sep. 28, 19981492.001 98 RTA00000616F.f.10.3 M00005395D:B12 8939 Sep. 28, 19981492.001 99 RTA00001064F.p.15.1 M00006840A:A12 8940 Sep. 28, 19981492.001 100 RTA00000617F.p.10.2 M00005516D:F12 8941 Sep. 28, 19981492.001 101 RTA00001076F.m.01.1 M00006925B:B02 8942 Sep. 28, 19981492.001 102 RTA00001075F.f.15.1 M00005395C:C11 8943 Sep. 28, 19981492.001 103 RTA00001075F.e.23.1 M00005385B:A10 8944 Sep. 28, 19981492.001 104 RTA00001076F.f.12.1 M00006688C:C12 8945 Sep. 28, 19981492.001 105 RTA00001075F.g.21.1 M00005420C:E03 8946 Sep. 28, 19981492.001 106 RTA00001076F.g.18.1 M00006727A:H12 8947 Sep. 28, 19981492.001 107 RTA00001075F.d.24.1 M00005363D:C05 8948 Sep. 28, 19981492.001 108 RTA00001075F.e.02.1 M00005364C:A02 8949 Sep. 28, 19981492.001 109 RTA00001075F.m.14.1 M00005563C:D05 8950 Sep. 28, 19981492.001 110 RTA00001064F.h.07.1 M00005520A:H11 8951 Sep. 28, 19981492.001 111 RTA00001065F.b.07.1 M00006936C:G11 8952 Sep. 28, 19981492.001 112 RTA00001065F.b.23.1 M00006968D:H02 8953 Sep. 28, 19981492.001 113 RTA00001064F.g.15.1 M00005497C:G08 8954 Sep. 28, 19981492.001 114 RTA00001064F.d.14.1 M00005390C:E05 8955 Sep. 28, 19981492.001 115 RTA00001064F.l.22.2 M00006595C:B08 8956 Sep. 28, 19981492.001 116 RTA00001064F.p.04.1 M00006816D:D08 8957 Sep. 28, 19981492.001 117 RTA00001076F.g.04.1 M00006712A:F01 8958 Sep. 28, 19981492.001 118 RTA00001075F.p.17.1 M00005709D:H05 8959 Sep. 28, 19981492.001 119 RTA00001075F.l.03.1 M00005505B:D10 8960 Sep. 28, 19981492.001 120 RTA00001076F.l.23.1 M00006925A:B09 8961 Sep. 28, 19981492.001 121 RTA00001076F.k.11.1 M00006874D:E01 8962 Sep. 28, 19981492.001 122 RTA00001076F.n.15.1 M00006994A:C12 8963 Sep. 28, 19981492.001 123 RTA00001075F.o.10.1 M00005629B:G06 8964 Sep. 28, 19981492.001 124 RTA00001075F.n.04.1 M00005589B:H12 8965 Sep. 28, 19981492.001 125 RTA00001075F.f.06.1 M00005388B:B02 8966 Sep. 28, 19981492.001 126 RTA00001076F.j.05.1 M00006823A:H06 8967 Sep. 28, 19981492.001 127 RTA00001076F.o.18.1 M00007041C:C05 8968 Sep. 28, 19981492.001 128 RTA00001064F.j.14.1 M00005648C:C11 8969 Sep. 28, 19981492.001 129 RTA00001064F.d.06.1 M00005376B:E08 8970 Sep. 28, 19981492.001 130 RTA00001077F.d.10.1 M00007200A:B12 8971 Sep. 28, 19981492.001 131 RTA00001065F.d.19.1 M00007109D:G01 8972 Sep. 28, 19981492.001 132 RTA00001064F.f.13.1 M00005464D:D07 8973 Sep. 28, 19981492.001 133 RTA00001075F.k.20.1 M00005493D:H12 8974 Sep. 28, 19981492.001 134 RTA00001075F.k.07.1 M00005479C:A05 8975 Sep. 28, 19981492.001 135 RTA00001075F.a.14.1 M00004847D:G01 8976 Sep. 28, 19981492.001 136 RTA00001076F.f.22.1 M00006704A:C11 8977 Sep. 28, 19981492.001 137 RTA00001076F.m.11.1 M00006949B:C07 8978 Sep. 28, 19981492.001 138 RTA00001064F.i.13.2 M00005618C:H11 8979 Sep. 28, 19981492.001 139 RTA00001076F.f.19.3 M00006694D:G06 8980 Sep. 28, 19981492.001 140 RTA00001076F.c.23.1 M00006617A:A06 8981 Sep. 28, 19981492.001 141 RTA00001077F.a.09.1 M00007107C:D02 8982 Sep. 28, 19981492.001 142 RTA00001064F.b.14.1 M00005020B:D10 8983 Sep. 28, 19981492.001 143 RTA00001075F.e.21.1 M00005382A:G09 8984 Sep. 28, 19981492.001 144 RTA00001075F.p.15.1 M00005705D:G09 8985 Sep. 28, 19981492.001 145 RTA00001076F.n.11.1 M00006991B:E05 8986 Sep. 28, 19981492.001 146 RTA00001065F.e.18.1 M00007161C:D12 8987 Sep. 28, 19981492.001 147 RTA00000615F.e.06.2 M00004871C:C04 8988 Sep. 28, 19981492.001 148 RTA00001064F.a.04.2 M00004821D:C03 8989 Sep. 28, 19981492.001 149 RTA00001075F.j.18.1 M00005469A:D10 8990 Sep. 28, 19981492.001 150 RTA00001077F.c.05.1 M00007156D:E11 8991 Sep. 28, 19981492.001 151 RTA00001075F.g.22.1 M00005420C:E10 8992 Sep. 28, 19981492.001 152 RTA00001077F.a.08.1 M00007104D:D10 8993 Sep. 28, 19981492.001 153 RTA00001077F.c.15.1 M00007172D:H03 8994 Sep. 28, 19981492.001 154 RTA00001077F.c.16.1 M00007175B:B11 8995 Sep. 28, 19981492.001 155 RTA00001077F.b.15.1 M00007141A:G08 8996 Sep. 28, 19981492.001 156 RTA00001077F.c.17.1 M00007175D:G02 8997 Sep. 28, 19981492.001 157 RTA00001077F.a.14.1 M00007116A:C08 8998 Sep. 28, 19981492.001 158 RTA00001075F.i.02.1 M00005438D:A08 8999 Sep. 28, 19981492.001 159 RTA00001075F.l.11.1 M00005509D:G05 9000 Sep. 28, 19981492.001 160 RTA00001064F.d.20.1 M00005403A:D12 9001 Sep. 28, 19981492.001 161 RTA00001076F.h.10.1 M00006740A:A06 9002 Sep. 28, 19981492.001 162 RTA00001075F.k.21.1 M00005494C:F08 9003 Sep. 28, 19981492.001 163 RTA00001075F.i.21.1 M00005450C:G09 9004 Sep. 28, 19981492.001 164 RTA00001076F.p.24.1 M00007093C:C11 9005 Sep. 28, 19981492.001 165 RTA00001075F.f.03.1 M00005385D:B08 9006 Sep. 28, 19981492.001 166 RTA00001065F.d.18.2 M00007107A:H08 9007 Sep. 28, 19981492.001 167 RTA00001076F.o.05.1 M00007026A:A03 9008 Sep. 28, 19981492.001 168 RTA00001075F.d.10.1 M00005353C:H01 9009 Sep. 28, 19981492.001 169 RTA00001064F.d.07.1 M00005378B:B04 9010 Sep. 28, 19981492.001 170 RTA00001065F.b.11.1 M00006945D:A07 9011 Sep. 28, 19981492.001 171 RTA00001076F.g.17.1 M00006726D:H10 9012 Sep. 28, 19981492.001 172 RTA00001065F.a.21.1 M00006918D:G08 9013 Sep. 28, 19981492.001 173 RTA00001077F.d.12.1 M00007203C:E06 9014 Sep. 28, 19981492.001 174 RTA00001064F.g.08.1 M00005481C:H05 9015 Sep. 28, 19981492.001 175 RTA00001064F.f.02.1 M00005449D:D04 9016 Sep. 28, 19981492.001 176 RTA00001075F.a.02.1 M00004825A:G12 9017 Sep. 28, 19981492.001 177 RTA00001064F.b.16.1 M00005296B:H07 9018 Sep. 28, 19981492.001 178 RTA00001077F.c.02.1 M00007152A:A10 9019 Sep. 28, 19981492.001 179 RTA00001064F.g.04.1 M00005480C:A04 9020 Sep. 28, 19981492.001 180 RTA00001075F.c.12.1 M00005305A:H01 9021 Sep. 28, 19981492.001 181 RTA00001064F.o.04.1 M00006752C:D04 9022 Sep. 28, 19981492.001 182 RTA00001077F.a.21.1 M00007121A:G04 9023 Sep. 28, 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8, 1998 1495.001 143RTA00001078F.d.18.1 M00008044B:F07 9648 Oct. 8, 1998 1495.001 144RTA00001068F.e.05.1 M00022904D:D04 9649 Oct. 8, 1998 1495.001 145RTA00001078F.i.18.1 M00021674A:B07 9650 Oct. 8, 1998 1495.001 146RTA00001066F.e.01.1 M00008054C:C03 9651 Oct. 8, 1998 1495.001 147RTA00001078F.n.14.2 M00021949D:A05 9652 Oct. 8, 1998 1495.001 148RTA00001067F.i.17.1 M00022413B:D07 9653 Oct. 8, 1998 1495.001 149RTA00001079F.l.19.1 M00022278C:E04 9654 Oct. 8, 1998 1495.001 150RTA00001081F.l.12.2 M00022923A:A09 9655 Oct. 8, 1998 1495.001 151RTA00001067F.j.03.1 M00022420B:C08 9656 Oct. 8, 1998 1495.001 152RTA00001068F.d.19.1 M00022898C:H07 9657 Oct. 8, 1998 1495.001 153RTA00001081F.g.23.1 M00022853D:C05 9658 Oct. 8, 1998 1495.001 154RTA00001081F.h.16.1 M00022860A:A07 9659 Oct. 8, 1998 1495.001 155RTA00001079F.i.05.1 M00022192B:H07 9660 Oct. 8, 1998 1495.001 156RTA00001068F.f.12.1 M00023012A:C06 9661 Oct. 8, 1998 1495.001 157RTA00001067F.e.09.1 M00022235D:F07 9662 Oct. 8, 1998 1495.001 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M00021668D:G09 9678 Oct. 8, 1998 1495.001 174RTA00001066F.a.11.1 M00007947B:F07 9679 Oct. 8, 1998 1495.001 175RTA00001078F.k.02.2 M00021846B:F05 9680 Oct. 8, 1998 1495.001 176RTA00001066F.h.04.1 M00021669B:G02 9681 Oct. 8, 1998 1495.001 177RTA00001066F.c.21.1 M00008015B:D08 9682 Oct. 8, 1998 1495.001 178RTA00001080F.h.06.1 M00022544C:D08 9683 Oct. 8, 1998 1495.001 179RTA00001067F.c.16.1 M00022177D:G02 9684 Oct. 8, 1998 1495.001 180RTA00001080F.f.21.1 M00022522B:A05 9685 Oct. 8, 1998 1495.001 181RTA00001080F.a.10.1 M00022425A:F11 9686 Oct. 8, 1998 1495.001 182RTA00001081F.o.10.1 M00023034B:B10 9687 Oct. 8, 1998 1495.001 183RTA00001078F.b.17.1 M00008001A:G11 9688 Oct. 8, 1998 1495.001 184RTA00001078F.g.04.1 M00008094D:C02 9689 Oct. 8, 1998 1495.001 185RTA00001080F.p.05.1 M00022704A:H08 9690 Oct. 8, 1998 1495.001 186RTA00001067F.f.04.1 M00022256D:G11 9691 Oct. 8, 1998 1495.001 187RTA00001066F.c.11.1 M00008003B:F09 9692 Oct. 8, 1998 1495.001 188RTA00001081F.b.19.1 M00022743C:G05 9693 Oct. 8, 1998 1495.001 189RTA00001081F.p.14.1 M00023097C:D10 9694 Oct. 8, 1998 1495.001 190RTA00001067F.k.16.1 M00022467C: H07 9695 Oct. 8, 1998 1495.001 191RTA00001081F.b.11.1 M00022737D:B02 9696 Oct. 8, 1998 1495.001 192RTA00001080F.k.12.1 M00022601A:A09 9697 Oct. 8, 1998 1495.001 193RTA00001066F.a.08.1 M00007943C:B02 9698 Oct. 8, 1998 1495.001 194RTA00001081F.b.10.1 M00022737B:F12 9699 Oct. 8, 1998 1495.001 195RTA00001080F.d.15.1 M00022488C:H02 9700 Oct. 8, 1998 1495.001 196RTA00001079F.p.04.1 M00022399D:A07 9701 Oct. 8, 1998 1495.001 197RTA00001067F.e.23.1 M00022251A:F07 9702 Oct. 8, 1998 1495.001 198RTA00001068F.a.08.1 M00022684C:C12 9703 Oct. 8, 1998 1495.001 199RTA00001078F.h.16.1 M00021628C:B09 9704 Oct. 8, 1998 1495.001 200RTA00001081F.g.18.1 M00022848D:H09 9705 Oct. 8, 1998 1495.001 201RTA00001081F.m.15.1 M00022968D:G06 9706 Oct. 8, 1998 1495.001 202RTA00001067F.k.09.1 M00022459C:G05 9707 Oct. 8, 1998 1495.001 203RTA00001080F.g.04.1 M00022527B:H05 9708 Oct. 8, 1998 1495.001 204RTA00001081F.j.19.2 M00022902C:F11 9709 Oct. 8, 1998 1495.001 205RTA00001081F.o.03.1 M00023023B:A05 9710 Oct. 8, 1998 1495.001 206RTA00001079F.b.23.1 M00022067A:B03 9711 Oct. 8, 1998 1495.001 207RTA00001078F.n.16.2 M00021951B:A01 9712 Oct. 8, 1998 1495.001 208RTA00001067F.b.01.1 M00022134D:D12 9713 Oct. 8, 1998 1495.001 209RTA00001080F.a.17.1 M00022435C:C05 9714 Oct. 8, 1998 1495.001 210RTA00001080F.c.17.1 M00022469A:A05 9715 Oct. 8, 1998 1495.001 211RTA00001068F.f.10.1 M00023003C:C10 9716 Oct. 8, 1998 1495.001 212RTA00001081F.h.18.1 M00022861C:B04 9717 Oct. 8, 1998 1495.001 213RTA00001066F.p.19.1 M00022106D:B06 9718 Oct. 8, 1998 1495.001 214RTA00001080F.c.09.1 M00022464D:F12 9719 Oct. 8, 1998 1495.001 215RTA00001078F.c.12.1 M00008014C:H01 9720 Oct. 8, 1998 1495.001 216RTA00001080F.l.10.1 M00022622A:E08 9721 Oct. 8, 1998 1495.001 217RTA00001078F.g.11.1 M00008099A:C12 9722 Oct. 8, 1998 1495.001 218RTA00001068F.f.09.1 M00023003A:H01 9723 Oct. 8, 1998 1495.001 219RTA00001067F.f.10.1 M00022261C:D06 9724 Oct. 8, 1998 1495.001 220RTA00001080F.o.05.1 M00022687C:C11 9725 Oct. 8, 1998 1495.001 221RTA00001078F.h.04.1 M00021620D:B06 9726 Oct. 8, 1998 1495.001 222RTA00001078F.p.03.2 M00021981D:A11 9727 Oct. 8, 1998 1495.001 223RTA00001080F.e.20.1 M00022510A:B09 9728 Oct. 8, 1998 1495.001 224RTA00001078F.k.19.2 M00021861C:B08 9729 Oct. 8, 1998 1495.001 225RTA00001078F.d.20.1 M00008045A:B05 9730 Oct. 8, 1998 1495.001 226RTA00001078F.b.22.1 M00008006A:H02 9731 Oct. 8, 1998 1495.001 227RTA00001068F.a.13.1 M00022701C:A05 9732 Oct. 8, 1998 1495.001 228RTA00001080F.m.16.1 M00022641D:F08 9733 Oct. 8, 1998 1495.001 229RTA00001080F.o.22.1 M00022702A:D10 9734 Oct. 8, 1998 1495.001 230RTA00001080F.k.16.1 M00022604A:F06 9735 Oct. 8, 1998 1495.001 231RTA00001067F.d.04.1 M00022199A:F09 9736 Oct. 8, 1998 1495.001 232RTA00001067F.k.10.1 M00022460C:E12 9737 Oct. 8, 1998 1495.001 233RTA00001078F.n.04.2 M00021931B:F04 9738 Oct. 8, 1998 1495.001 234RTA00001078F.n.07.2 M00021945A:B04 9739 Oct. 8, 1998 1495.001 235RTA00001081F.a.16.1 M00022725D:G05 9740 Oct. 8, 1998 1495.001 236RTA00001078F.l.13.2 M00021879B:C11 9741 Oct. 8, 1998 1495.001 237RTA00001078F.f.13.1 M00008082B:C05 9742 Oct. 8, 1998 1495.001 238RTA00001079F.d.05.1 M00022087D:F12 9743 Oct. 8, 1998 1495.001 239RTA00001067F.i.13.1 M00022406C:G03 9744 Oct. 8, 1998 1495.001 240RTA00001068F.d.23.1 M00022902B:F10 9745 Oct. 8, 1998 1495.001 241RTA00001078F.c.13.1 M00008014D:A11 9746 Oct. 8, 1998 1495.001 242RTA00001078F.a.18.1 M00007969B:E10 9747 Oct. 8, 1998 1495.001 243RTA00001068F.b.23.1 M00022765B:E03 9748 Oct. 8, 1998 1495.001 244RTA00001078F.f.21.1 M00008085B:G01 9749 Oct. 8, 1998 1495.001 245RTA00001067F.b.15.1 M00022144D:D09 9750 Oct. 8, 1998 1495.001 246RTA00001078F.o.04.2 M00021963C:H04 9751 Oct. 8, 1998 1495.001 247RTA00001081F.e.14.1 M00022817D:B09 9752 Oct. 8, 1998 1495.001 248RTA00001078F.k.04.2 M00021847B:A09 9753 Oct. 8, 1998 1495.001 249RTA00001079F.g.15.2 M00022158C:C08 9754 Oct. 8, 1998 1495.001 250RTA00001067F.k.23.1 M00022477C:C07 9755 Oct. 8, 1998 1495.001 251RTA00001079F.h.08.2 M00022176A:F02 9756 Oct. 8, 1998 1495.001 252RTA00001078F.d.17.1 M00008028D:B01 9757 Oct. 8, 1998 1495.001 253RTA00001067F.d.07.1 M00022203B:A05 9758 Oct. 8, 1998 1495.001 254RTA00001068F.e.04.1 M00022903D:H02 9759 Oct. 8, 1998 1495.001 255RTA00001068F.a.06.1 M00022682A:F10 9760 Oct. 8, 1998 1495.001 256RTA00001078F.e.10.1 M00008054C:E07 9761 Oct. 8, 1998 1495.001 257RTA00001079F.b.11.1 M00022056B:G12 9762 Oct. 8, 1998 1495.001 258RTA00001066F.h.11.1 M00021676B:B12 9763 Oct. 8, 1998 1495.001 259RTA00001079F.d.01.1 M00022084B:C03 9764 Oct. 8, 1998 1495.001 260RTA00001067F.g.14.1 M00022363C:D03 9765 Oct. 8, 1998 1495.001 261RTA00001066F.g.06.1 M00021625B:G07 9766 Oct. 8, 1998 1495.001 262RTA00001081F.j.09.2 M00022893D:C06 9767 Oct. 8, 1998 1495.001 263RTA00001068F.e.19.1 M00022963A:E07 9768 Oct. 8, 1998 1495.001 264RTA00001079F.l.21.1 M00022282A:A11 9769 Oct. 8, 1998 1495.001 265RTA00001078F.h.09.1 M00021624B:E11 9770 Oct. 8, 1998 1495.001 266RTA00001078F.d.16.1 M00008027D:H09 9771 Oct. 8, 1998 1495.001 267RTA00001079F.g.22.2 M00022167B:H02 9772 Oct. 8, 1998 1495.001 268RTA00001066F.e.15.1 M00008075D:B01 9773 Oct. 8, 1998 1495.001 269RTA00001080F.g.16.1 M00022538D:B02 9774 Oct. 8, 1998 1495.001 270RTA00001080F.b.07.1 M00022447A:H06 9775 Oct. 8, 1998 1495.001 271RTA00001078F.n.21.2 M00021958A:A03 9776 Oct. 8, 1998 1495.001 272RTA00001078F.b.12.1 M00007998C:B04 9777 Oct. 8, 1998 1495.001 273RTA00001066F.p.01.2 M00022099C:A10 9778 Oct. 8, 1998 1495.001 274RTA00001066F.o.22.1 M00022095C:F03 9779 Oct. 8, 1998 1495.001 275RTA00001080F.i.19.1 M00022568B:D03 9780 Oct. 8, 1998 1495.001 276RTA00001079F.g.01.1 M00022138C:B07 9781 Oct. 8, 1998 1495.001 277RTA00001079F.e.02.1 M00022102D:A10 9782 Oct. 8, 1998 1495.001 278RTA00001079F.k.01.1 M00022233C:D11 9783 Oct. 8, 1998 1495.001 279RTA00001079F.o.11.1 M00022386D:C04 9784 Oct. 8, 1998 1495.001 280RTA00001068F.d.02.1 M00022834A:H02 9785 Oct. 8, 1998 1495.001 281RTA00001078F.a.07.1 M00007939A:F06 9786 Oct. 8, 1998 1495.001 282RTA00001081F.b.20.1 M00022743C:G06 9787 Oct. 8, 1998 1495.001 283RTA00001067F.f.20.1 M00022273A:B03 9788 Oct. 8, 1998 1495.001 284RTA00001079F.c.06.1 M00022072D:E12 9789 Oct. 8, 1998 1495.001 285RTA00001068F.b.24.1 M00022768A:A10 9790 Oct. 8, 1998 1495.001 286RTA00001080F.o.08.1 M00022691A:G01 9791 Oct. 8, 1998 1495.001 287RTA00001078F.j.10.2 M00021687C:A04 9792 Oct. 8, 1998 1495.001 288RTA00001080F.b.03.1 M00022444B:C04 9793 Oct. 8, 1998 1495.001 289RTA00001067F.e.13.1 M00022240C:B03 9794 Oct. 8, 1998 1495.001 290RTA00001081F.h.05.1 M00022856A:B09 9795 Oct. 8, 1998 1495.001 291RTA00001067F.f.01.1 M00022252C:A04 9796 Oct. 8, 1998 1495.001 292RTA00001080F.g.23.1 M00022542A:B06 9797 Oct. 8, 1998 1495.001 293RTA00001080F.h.16.1 M00022548A:F02 9798 Oct. 8, 1998 1495.001 294RTA00001080F.f.15.1 M00022517C:B01 9799 Oct. 8, 1998 1495.001 295RTA00001080F.f.06.1 M00022513C:E10 9800 Oct. 8, 1998 1495.001 296RTA00001081F.a.04.2 M00022716A:C01 9801 Oct. 8, 1998 1495.001 297RTA00001078F.p.16.2 M00022001B:H10 9802 Oct. 8, 1998 1495.001 298RTA00001081F.b.03.1 M00022734C:A03 9803 Oct. 8, 1998 1495.001 299RTA00001080F.a.21.1 M00022441B:A06 9804 Oct. 8, 1998 1495.001 300RTA00001079F.f.05.1 M00022127C:E01 9805 Oct. 8, 1998 1495.001 301RTA00001080F.n.23.1 M00022681D:H10 9806 Oct. 8, 1998 1495.001 302RTA00001078F.c.18.1 M00008016C:E06 9807 Oct. 8, 1998 1495.001 303RTA00001068F.a.11.1 M00022697A:C08 9808 Oct. 8, 1998 1495.001 304RTA00001068F.g.09.1 M00023095C:A09 9809 Oct. 8, 1998 1495.001 305RTA00001068F.a.22.1 M00022709A:C01 9810 Oct. 8, 1998 1495.001 306RTA00001079F.h.09.2 M00022176D:F05 9811 Oct. 8, 1998 1495.001 307RTA00001079F.h.01.2 M00022169A:E11 9812 Oct. 8, 1998 1495.001 308RTA00001078F.g.07.1 M00008097C:E04 9813 Oct. 8, 1998 1495.001 309RTA00001078F.m.08.2 M00021908B:F03 9814 Oct. 8, 1998 1495.001 310RTA00001080F.a.03.1 M00022417B:C01 9815 Oct. 8, 1998 1495.001 311RTA00001079F.o.06.1 M00022384B:E06 9816 Oct. 8, 1998 1495.001 312RTA00001079F.p.06.1 M00022401C:G07 9817 Oct. 8, 1998 1495.001 313RTA00001078F.p.18.2 M00022001D:E06 9818 Oct. 8, 1998 1495.001 314RTA00001068F.a.17.1 M00022705B:F08 9819 Oct. 8, 1998 1495.001 315RTA00001078F.a.10.1 M00007948C:G01 9820 Oct. 8, 1998 1495.001 316RTA00001079F.h.20.2 M00022184D:H07 9821 Oct. 8, 1998 1495.001 317RTA00001081F.n.03.1 M00022986B:C02 9822 Oct. 8, 1998 1495.001 318RTA00001080F.c.04.1 M00022460D:C07

Example 46 Results of Public Database Search to Identify Function ofGene Products

SEQ ID NOS:8841-9919 were translated in all three reading frames, andthe nucleotide sequences and translated amino acid sequences used asquery sequences to search for homologous sequences in either the GenBank(nucleotide sequences) or Non-Redundant Protein (amino acid sequences)databases. Query and individual sequences were aligned using the BLAST2.0 programs, available over the world wide web. (see also Altschul, etal. Nucleic Acids Res. (1997) 25:3389-3402). The sequences were maskedto various extents to prevent searching of repetitive sequences orpoly-A sequences, using the XBLAST program for masking low complexity asdescribed above.

Tables 70A and 70B (inserted before the claims) provide the alignmentsummaries having a p value of 1×10⁻² or less indicating substantialhomology between the sequences of the present invention and those of theindicated public databases. Table 70A provides the SEQ ID NO of thequery sequence, the accession number of the GenBank database entry ofthe homologous sequence, and the p value of the alignment. Table 70Aprovides the SEQ ID NO of the query sequence, the accession number ofthe Non-Redundant Protein database entry of the homologous sequence, andthe p value of the alignment. The alignments provided in Tables 70A and70B are the best available alignment to a DNA or amino acid sequence ata time just prior to filing of the present specification. The activityof the polypeptide encoded by the SEQ ID NOS listed in Tables 70A and70B can be extrapolated to be substantially the same or substantiallysimilar to the activity of the reported nearest neighbor or closelyrelated sequence. The accession number of the nearest neighbor isreported, providing a publicly available reference to the activities andfunctions exhibited by the nearest neighbor. The public informationregarding the activities and functions of each of the nearest neighborsequences is incorporated by reference in this application. Alsoincorporated by reference is all publicly available informationregarding the sequence, as well as the putative and actual activitiesand functions of the nearest neighbor sequences listed in Table 70 andtheir related sequences. The search program and database used for thealignment, as well as the calculation of the p value are also indicated.

Full length sequences or fragments of the polynucleotide sequences ofthe nearest neighbors can be used as probes and primers to identify andisolate the full length sequence of the corresponding polynucleotide.The nearest neighbors can indicate a tissue or cell type to be used toconstruct a library for the full-length sequences of the correspondingpolynucleotides.

Example 47 Identification of Contiguous Sequences Having aPolynucleotide of the Invention

The novel polynucleotides were used to screen publicly available andproprietary databases to determine if any of the polynucleotides of SEQID NOS:8841-9785 would facilitate identification of a contiguoussequence, e.g., the polynucleotides would provide sequence that wouldresult in 5′ extension of another DNA sequence, resulting in productionof a longer contiguous sequence composed of the provided polynucleotideand the other DNA sequence(s). Contiging was performed using theGelmerge application (default settings) of GCG from the Univ. ofWisconsin.

Using these parameters, 83 contiged sequences were generated. Thesecontiged sequences are provided as SEQ ID NOS:9800-9882 (see Table 69C).Table 69C provides the SEQ ID NO of the contig sequence, the name of thesequence used to create the contig, and the accession number of thepublicly available tentative human consensus (THC) sequence used withthe sequence of the corresponding sequence name to provide the contig.The sequence name of Table 69C can be correlated with the SEQ ID NO: ofthe polynucleotide used to generate the contig by referring to Tables69A and 69B.

The contiged sequences (SEQ ID NOS: 9800-9882) represent longersequences that encompass another of the polynucleotide sequence of theinvention. The contiged sequences were then translated in all threereading frames to determine the best alignment with individual sequencesusing the BLAST programs as described above. The sequences were maskedusing the XBLAST program for masking low complexity as described above.As described in more detail below, several of the contiged sequenceswere found to encode polypeptides having characteristics of apolypeptide belonging to a known protein families (and thus representnew members of these protein families) and/or comprising a knownfunctional domain (see Example 4 and Table 71 below). Thus the inventionencompasses fragments, fusions, and variants of such polynucleotidesthat retain biological activity associated with the protein familyand/or functional domain identified herein.

Example 48 Members of Protein Families

SEQ ID NOS:8841-9919 were used to conduct a profile search as describedin the specification above. Several of the polynucleotides of theinvention were found to encode polypeptides having characteristics of apolypeptide belonging to a known protein family (and thus representmembers of these protein families) and/or comprising a known functionaldomain. Table 71 (inserted before claims) provides the SEQ ID NO: of thequery sequence, a brief description of the profile hit, the position ofthe query sequence within the individual sequence (indicated as “start”and “stop”), and the orientation (Direction, “Dir”) of the querysequence with respect to the individual sequence, where forward (for)indicates that the alignment is in the same direction (left to right) asthe sequence provided in the Sequence Listing and reverse (rev)indicates that the alignment is with a sequence complementary to thesequence provided in the Sequence Listing.

Some polynucleotides exhibited multiple profile hits where the querysequence contains overlapping profile regions, and/or where the sequencecontains two different functional domains. Each of the profile hits ofTable 71 are described in more detail below. The acronyms for theprofiles (provided in parentheses) are those used to identify theprofile in the Pfam and Prosite databases. The public informationavailable on the Pfam and Prosite databases regarding the variousprofiles, including but not limited to the activities, function, andconsensus sequences of various proteins families and protein domains, isincorporated herein by reference. TABLE 71 SEQ ID NO: Profilename StartStop Direction 8937 Kazal 25 243 for 9067 helicase_C 212 389 for 9082EFhand 275 310 for 9290 SH3 44 226 for 9313 Zincfing_C2H2 211 273 for9345 WD_domain 80 178 for 9352 Zincfing_C2H2 147 209 for 9363 PDZ 168395 for 9367 ras 18 395 for 9385 ANK 311 393 for 9387 Ets_Nterm 7 237for 9446 WW_domain 120 209 for 9475 protkinase 47 400 for 9475 mkk 41394 for 9476 trypsin 147 381 for 9480 Zincfing_C2H2 122 184 for 9533Zincfing_CCHC 135 185 for 9561 WD_domain 18 116 for 9645 Zincfing_C3HC4263 406 for 9758 BZIP 51 224 for 9759 Zincfing_C2H2 125 187 for 9765 FKH9 230 for 9811 Zincfing_C2H2 202 264 for 9813 Zincfing_CCHC 262 309 for9820 PDZ 241 468 for 9832 mkk 0 708 for 9832 protkinase 121 711 for 9835trypsin 202 760 for 9824 trypsin 202 760 for 9858 WD_domain 18 116 for9868 pr55 24 1293 for 9875 ATPases 74 616 for 9876 Zincfing_C2H2 122 184for 9893 14_3_3 63 619 for 9898 helicase_C 212 448 for 9898 ATPases 59442 for 9903 Zincfing_C2H2 211 273 for 9906 Zincfing_C2H2 125 187 for9912 ATPases 808 1284 for 9918 protkinase 309 1022 rev 9918 neur_chan 12508 rev 9918 Zincfing_CCHC 262 309 for 9918 Zincfing_C3HC4 557 679 for

14-3-3 Family (14_(—)3_(—)3; Pfam Pfam Accession No. PF00244). One SEQID NO corresponds to a sequence encoding a 14-3-3 protein family member.The 14-3-3 protein family includes a group of closely related acidichomodimeric proteins of about 30 kD first identified as very abundant inmammalian brain tissues and located preferentially in neurons (Aitken etal. Trends Biochem. Sci. (1995) 20:95-97; Morrison Science (1994)266:56-57; and Xiao et al. Nature (1995) 376:188-191). The 14-3-3proteins have multiple biological activities, including a key role insignal transduction pathways and the cell cycle. 14-3-3 proteinsinteract with kinases (e.g., PKC or Raf-1), and can also function asprotein-kinase dependent activators of tyrosine and tryptophanhydroxylases. The 14-3-3 protein sequences are extremely well conserved,and include two highly conserved regions: the first is a peptide of 11residues located in the N-terminal section; the second, a 20 amino acidregion located in the C-terminal section.

Ank Repeats (ANK; Pfam Accession No. PF0023). One SEQ ID NO represents apolynucleotide encoding an Ank repeat-containing protein. The ankyrinmotif is a 33 amino acid sequence named after the protein ankyrin whichhas 24 tandem 33-amino-acid motifs. Ank repeats were originallyidentified in the cell-cycle-control protein cdc10 (Breeden et al.,Nature (1987) 329:651). Proteins containing ankyrin repeats includeankyrin, myotropin, I-kappaB proteins, cell cycle protein cdc10, theNotch receptor (Matsuno et al., Development (1997) 124(21):4265); G9a(or BAT8) of the class III region of the major histocompatibilitycomplex (Biochem J. 290:811-818, 1993), FABP, GABP, 53BP2, Lin12, glp-1,SW14, and SW16. The functions of the ankyrin repeats are compatible witha role in protein-protein interactions (Bork, Proteins (1993) 17(4):363;Lambert and Bennet, Eur. J. Biochem. (1993) 211:1; Kerr et al., CurrentOp. Cell Biol. (1992) 4:496; Bennet et al., J. Biol. Chem. (1980)255:6424).

ATPases Associated with Various Cellular Activities (ATPases; PfamAccession No. PF0004). Some SEQ ID NOS corresond to a sequence thatencodes a member of a family of ATPases Associated with diverse cellularActivities (AAA). The AAA protein family is composed of a large numberof ATPases that share a conserved region of about 220 amino acidscontaining an ATP-binding site (Froehlich et al, J. Cell Biol. (1991)114:443; Erdmann et al. Cell (1991) 64:499; Peters et al., EMBO J.(1990) 9:1757; Kunau et al., Biochimie (1993) 75:209-224; Confalonieriet al., BioEssays (1995) 17:639). The AAA domain, which can be presentin one or two copies, acts as an ATP-dependent protein clamp(Confalonieri et al. (1995) BioEssays 17:639) and contains a highlyconserved region located in the central part of the domain.

Basic Region Plus Leucine Zipper Transcription Factors (BZIP; PfamAccession No. PF00170). One SEQ ID NO represents a polynucleotideencoding a novel member of the family of basic region plus leucinezipper transcription factors. The bZIP superfamily (Hurst, Protein Prof.(1995) 2:105; and Ellenberger, Curr. Opin. Struct. Biol. (1994) 4:12) ofeukaryotic DNA-binding transcription factors encompasses proteins thatcontain a basic region mediating sequence-specific DNA-binding followedby a leucine zipper required for dimerization.

EF Hand (Efhand; Pfam Accession No. PF00036). One SEQ ID NO correspondsto a polynucleotide encoding a member of the EF-hand protein family, acalcium binding domain shared by many calcium-binding proteins belongingto the same evolutionary family (Kawasaki et al., Protein. Prof. (1995)2:305-490). The domain is a twelve residue loop flanked on both sides bya twelve residue alpha-helical domain, with a calcium ion coordinated ina pentagonal bipyramidal configuration. The six residues involved in thebinding are in positions 1, 3, 5, 7, 9 and 12; these residues aredenoted by X, Y, Z, −Y, −X and −Z. The invariant Glu or Asp at position12 provides two oxygens for liganding Ca (bidentate ligand).

Ets Domain (Ets_Nterm; Pfam Accession No. PF110178). One SEQ ID NO, andthus the sequence it validates, represents a polynucleotide encoding apolypeptide with N-terminal homology in ETS domain. Proteins of thisfamily contain a conserved domain, the “ETS-domain,” that is involved inDNA binding. The domain appears to recognize purine-rich sequences; itis about 85 to 90 amino acids in length, and is rich in aromatic andpositively charged residues (Wasylyk, et al., Eur. J. Biochem. (1993)211:718). The ets gene family encodes a novel class of DNA-bindingproteins, each of which binds a specific DNA sequence and comprises anets domain that specifically interacts with sequences containing thecommon core tri-nucleotide sequence GGA. In addition to an ets domain,native ets proteins comprise other sequences which can modulate thebiological specificity of the protein. Ets genes and proteins areinvolved in a variety of essential biological processes including cellgrowth, differentiation and development, and three members areimplicated in oncogenic process.

(FKH; Pfam Accession No. PF00250). One SEQ. ID NO corresponds to a geneencoding a polypeptide comprising a forkhead domain. The forkhead domain(also known as a “winged helix”) is present in a family of eukaryotictranscription factors, and is a conserved domain of about 100 amino acidresidues that is involved in DNA-binding (Weigel et al. Cell (1990)63:455-456; Clark et al. Nature (1993) 364:412-420). Mammalian genesthat comprise a forkhead domain include those encoding: 1)transcriptional activators (e.g., HNF-3-alpha, -beta, and -gammaproteins, which interact with the cis-acting regulatory regions of anumber of liver genes); 2) interleukin-enhancer binding factor (ILF),which binds to purine-rich NFAT-like motifs in the HIV-1 LTR and theinterleukin-2 promoter and is involved in both positive and negativeregulation of important viral and cellular promoter elements; 3)transcription factor BF-1, which plays an important role in theestablishment of the regional subdivision of the developing-brain and inthe development of the telencephalon; 4) human HTLF, which binds to thepurine-rich region in human T-cell leukemia virus long terminal repeat(HTLV-I LTR); 5) transcription factors FREAC-1 (FKHL5, HFH-8), FREAC-2(FKHL6), FREAC-3 (FKHL7, FKH-1), FREAC-4 (FKHL8), FREAC-5 (FKHL9, FKH-2,HFH-6), FREAC-6 (FKHL10, HFH-5), FREAC-7 (FKHL11), FREAC-8 (FKHL12,HFH-7), FKH-3, FKH-4, FKH-5, HFH-1 and HFH-4; 6) human AFX1 which isinvolved in a chromosomal translocation that causes acute leukemia; and7) human FKHR which is involved in a chromosomal translocation thatcauses rhabdomyosarcoma. The fork domain is highly conserved, and isdetected by two consensus patterns: the first corresponding to theN-terminal section of the domain; the second corresponding to aheptapeptide located in the central section of the domain.

Helicases conserved C-terminal domain (helicase C; Pfam Accession No.PF00271). Some SEQ ID NOS represent polynucleotides encoding novelmembers of the DEAD/H helicase family. The DEAD box family comprises anumber of eukaryotic and prokaryotic proteins involved in ATP-dependent,nucleic-acid unwinding. All DEAD box family members of the aboveproteins share a number of conserved sequence motifs, some of which arespecific to the DEAD family while others are shared by other ATP-bindingproteins or by proteins belonging to the helicases ‘superfamily’(Hodgman, Nature (1988) 333:22 and Nature (1988) 333:578;http://www.expasy.ch/www/linder/HELICASES_TEXT.html). One of thesemotifs, called the ‘D-E-A-D-box’, represents a special version of the Bmotif of ATP-binding proteins. Some other proteins belong to a subfamilywhich have His instead of the second Asp and are thus said to be‘D-E-A-H-box’ proteins (Wassarman D. A., et al., Nature (1991) 349:463;Harosh I., et al., Nucleic Acids Res. (1991) 19:6331; Koonin E. V., etal., J. Gen. Virol. (1992) 73:989).

Kazal serine protease inhibitors family signature (Kazal; Pfam AccessionNo. PF00050). One SEQ ID NO corresponds to a polynucleotide of a geneencoding a serine protease inhibitor of the Kazal inhibitor family(Laskowski et al. Annu. Rev. Biochem. (1980) 49:593-626). The basicstructure of Kazal serine protease inhibitors such a type of inhibitoris described at Pfam Accession No. PF00050. Exemplary proteins known tobelong to this family include: pancreatic secretory trypsin inhibitor(PSTI), whose physiological function is to prevent the trypsin-catalyzedpremature activation of zymogens within the pancreas; mammalian seminalacrosin inhibitors; canidae and felidae submandibular glanddouble-headed protease inhibitors, which contain two Kazal-type domains,the first one inhibits trypsin and the second one elastase; a mouseprostatic secretory glycoprotein, induced by androgens, and whichexhibits anti-trypsin activity; avian ovomucoids; chicken ovoinhibitor;and the leech trypsin inhibitor Bdellin B-3.

MAP kinase kinase (mkk). Some SEQ ID NOS represent members of the MAPkinase kinase (mkk) family. MAP kinases (MAPK) are involved in signaltransduction, and are important in cell cycle and cell growth controls.The MAP kinase kinases (MAPKK) are dual-specificity protein kinaseswhich phosphorylate and activate MAP kinases. MAPKK homologues have beenfound in yeast, invertebrates, amphibians, and mammals. Moreover, theMAPKK/MAPK phosphorylation switch constitutes a basic module activatedin distinct pathways in yeast and in vertebrates. MAPKKs are essentialtransducers through which signals must pass before reaching the nucleus.For review, see, e.g., Biologique Biol Cell (1993) 79:193-207; Nishidaet al., Trends Biochem Sci (1993) 18:128-31; Ruderman Curr Opin CellBiol (1993) 5:207-13; Dhanasekaran et al., Oncogene (1998) 17:1447-55;Kiefer et al., Biochem Soc Trans (1997) 25:491-8; and Hill, Cell Signal(1996) 8:533-44.

Neurotransmitter-Gated Ion-Channel (neur_chan, Pfam Accession No.PF00065). One SEQ ID NO corresponds to a sequence encoding aneurotransmitter-gated ion channel. Neurotransmitter-gated ion-channels,which provide the molecular basis for rapid signal transmission atchemical synapses, are post-synaptic oligomeric transmembrane complexesthat transiently form a ionic channel upon the binding of a specificneurotransmitter. Five types of neurotransmitter-gated receptors areknown: 1) nicotinic acetylcholine receptor (AchR); 2) glycine receptor;3) gamma-aminobutyric-acid (GABA) receptor; 4) serotonin 5HT3 receptor;and 5) glutamate receptor. All known sequences of subunits fromneurotransmitter-gated ion-channels are structurally related, and arecomposed of a large extracellular glycosylated N-terminal ligand-bindingdomain, followed by three hydrophobic transmembrane regions that formthe ionic channel, followed by an intracellular region of variablelength. A fourth hydrophobic region is found at the C-terminal of thesequence.

PDZ Domain (PDZ; Pfam Accession No. PF00595.) Some SEQ ID NOS correspondto a gene comprising a PDZ domain (also known as DHR or GLGF domain).PDZ domains comprise 80-100 residue repeats, several of which interactwith the C-terminal tetrapeptide motifs X-Ser/Thr-X-Val-COO— of ionchannels and/or receptors, and are found in mammalian proteins as wellas in bacteria, yeast, and plants (Pontig et al. Protein Sci (1997)6(2):464-8). Proteins comprising one or more PDZ domains are found indiverse membrane-associated proteins, including members of the MAGUKfamily of guanylate kinase homologues, several protein phosphatases andkinases, neuronal nitric oxide synthase, and severaldystrophin-associated proteins, collectively known as syntrophins(Ponting et al. Bioessays (1997) 19(6):469-79). Many PDZdomain-containing proteins are localised to highly specialisedsubmembranous sites, suggesting their participation in cellular junctionformation, receptor or channel clustering, and intracellular signallingevents. For example, PDZ domains of several MAGUKs interact with theC-terminal polypeptides of a subset of NMDA receptor subunits and/orwith Shaker-type K+ channels. Other PDZ domains have been shown to bindsimilar ligands of other transmembrane receptors. In celljunction-associated proteins, the PDZ mediates the clustering ofmembrane ion channels by binding to their C-terminus. The X-raycrystallographic structure of some proteins comrpising PDZ domains havebeen solved (see, e.g., Doyle et al. Cell (1996) 85(7):1067-76).

Protein phosphatase 2A regulatory subunit PR55 signatures (PR55; PfamAccession No. PF01240). One SEQ ID NO corresponds to a gene encoding aprotine phosphatase 2A reguatory subunit. Protein phosphatase 2A (PP2A)is a serine/threonine phosphatase involved in many aspects of cellularfunction including the regulation of metabolic enzymes and proteinsinvolved in signal transduction. PP2A is a trimeric enzyme that consistsof a core composed of a catalytic subunit associated with a 65 Kdregulatory subunit (PR65), also called subunit A; this complex thenassociates with a third variable subunit (subunit B), which confersdistinct properties to the holoenzyme (Mayer et al. Trends Cell Biol.(1994) 4:287-291). One of the forms of the variable subunit is a 55 Kdprotein (PR55) which is highly conserved in mammals (where threeisoforms are known to exist). This subunit may perform a substraterecognition function or be responsible for targeting the enzyme complexto the appropriate subcellular compartment.

Protein Kinase (protkinase; Pfam Accession No. PF00069). Some SEQ ID NOSrepresent polynucleotides encoding protein kinases, which catalyzephosphorylation of proteins in a variety of pathways, and are implicatedin cancer. Eukaryotic protein kinases (Hanks, et al., FASEB J. (1995)9:576; Hunter, Meth. Enzymol. (1991) 200:3; Hanks, et al., Meth.Enzymol. (1991) 200:38; Hanks, Curr. Opin. Struct. Biol. (1991) 1:369;Hanks et al., Science (1988) 241:42) belong to a very extensive familyof proteins that share a conserved catalytic core common to bothserine/threonine and tyrosine protein kinases. There are a number ofconserved regions in the catalytic domain of protein kinases. The firstregion, located in the N-terminal extremity of the catalytic domain, isa glycine-rich stretch of residues in the vicinity of a lysine residue,which has been shown to be involved in ATP binding. The second region,located in the central part of the catalytic domain, contains aconserved an aspartic acid residue that is important for the catalyticactivity of the enzyme (Knighton, et al., Science (1991) 253:407).

The protein kinase profile includes two signature patterns for thissecond region: one specific for serine/threonine kinases and the otherfor tyrosine kinases. A third profile is based on the alignment in(Hanks, et al., FASEB J. (1995) 9:576) and covers the entire catalyticdomain.

Ras family proteins (ras; Pfam Accession No. PF00071). One SEQ ID NOrepresents polynucleotides encoding the ras family of smallGTP/GDP-binding proteins (Valencia et al., 1991, Biochemistry30:4637-4648). Ras family members generally require a specific guaninenucleotide exchange factor (GEF) and a specific GTPase activatingprotein (GAP) as stimulators of overall GTPase activity. Amongras-related proteins, the highest degree of sequence conservation isfound in four regions that are directly involved in guanine nucleotidebinding. The first two constitute most of the phosphate and Mg2+ bindingsite (PM site) and are located in the first half of the G-domain. Theother two regions are involved in guanosine binding and are located inthe C-terminal half of the molecule. Motifs and conserved structuralfeatures of the ras-related proteins are described in Valencia et al.,1991, Biochemistry 30:4637-4648.

Src homology domain 3 (SH3; Pfam Accession No. PF00018). One SEQ ID NOcorresponds to a gene comprising a Src homology domain. The Src homology3 (SH3) domain is a small protein domain of about 60 amino acid residuesfirst identified as a conserved sequence in the non-catalytic part ofseveral cytoplasmic protein tyrosine kinases (e.g. Src, Abl, Lck) (Mayeret al. Nature (1988) 332:272-275). Since then, it has been found in agreat variety of other intracellular or membrane-associated proteins(Musacchio et al. FEBS Lett. (1992) 307:55-61; Pawson et al. Curr. Biol.(1993) 3:434-442; Mayer et al. Trends Cell Biol. (1993) 3:8-13; PawsonNature (1995) 373:573-580). The SH3 domain has a characteristic foldwhich consists of five or six beta-strands arranged as two tightlypacked anti-parallel beta sheets. The linker regions may contain shorthelices (Kuriyan et al. Curr. Opin. Struct. Biol. (1993) 3:828-837). TheSH3 domain is thought to mediate assembly of specific protein complexesvia binding to proline-rich peptides (Morton et al. Curr. Biol. (1994)4:615-617). In general SH3 domains are found as single copies in a givenprotein, but there a significant number of proteins comprise two SH3domains and a few comprise 3 or 4 copies. The profile to detect SH3domains is based on a structural alignment consisting of 5 gap-freeblocks and 4 linker regions totaling 62 match positions.

Trypsin (trypsin; Pfam Accession No. PF00089). Some SEQ ID NOScorrespond to novel serine proteases of the trypsin family. Thecatalytic activity of the serine proteases from the trypsin family isprovided by a charge relay system involving an aspartic acid residuehydrogen-bonded to a histidine, which itself is hydrogen-bonded to aserine. The sequences in the vicinity of the active site serine andhistidine residues are well conserved (Brenner Nature (1988) 334:528).

WD Domain, G-Beta Repeats (WD_domain; Pfam Accession No. PF00400). SomeSEQ ID NOS represent a members of the WD domain/G-beta repeat family.Beta-transducin (G-beta) is one of the three subunits (alpha, beta, andgamma) of the guanine nucleotide-binding proteins (G proteins) which actas intermediaries in the transduction of signals generated bytransmembrane receptors (Gilman, Annu. Rev. Biochem. (1987) 56:615). Thealpha subunit binds to and hydrolyzes GTP; the beta and gamma subunitsare required for the replacement of GDP by GTP as well as for membraneanchoring and receptor recognition. In higher eukaryotes, G-beta existsas a small multigene family of highly conserved proteins of about 340amino acid residues. Structurally, G-beta has eight tandem repeats ofabout 40 residues, each containing a central Trp-Asp motif (this type ofrepeat is sometimes called a WD-40 repeat).

WW/rsp5/WWP domain signature and profile (WW domain; Pfam Accession No.PF00397). One SEQ ID NO corresponds to a gene encoding a proteincomprising a WW domain. The WW domain (Bork et al. Trends Biochem. Sci.(1994) 19:531-533; Andre et al. Biochem. Biophys. Res. Commun. (1994)205:1201-1205; Hofmann et al. FEBS Lett. (1995) 358:153-157; Sudol etal. FEBS Lett. (1995) 369:67-71 (also known as rsp5 or WWP) wasdiscovered as a short conserved region in a number of unrelatedproteins, among them dystrophin, the gene responsible for Duchennemuscular dystrophy. The domain, which spans about 35 residues, isrepeated up to 4 times in some proteins. It has been shown (Chen et al.Proc. Natl. Acad. Sci. U.S.A. (1995) 92:7819-7823) to bind proteins withparticular proline-motifs, [AP]-P-P-[AP]-Y, and thus resembles somewhatSH3 domains. The WW domain conatins beta-strands grouped around fourconserved aromatic positions, generally tryptophan. The name WW or WWPderives from the presence of two tryptophane as well as a conservedproline. The WW domain is frequently associated with other domainstypical for proteins in signal transduction processes.

Zinc Finger, C2H2 Type (Zincfing_C2H2; Pfam Accession No. PF00096).Several sequences corresponded to polynucleotides encoding members ofthe C2H2 type zinc finger protein family, which contain zinc fingerdomains that facilitate nucleic acid binding (Klug et al., TrendsBiochem. Sci. (1987) 12:464; Evans et al., Cell (1988) 52:1; Payre etal., FEBS Lett. (1988) 234:245; Miller et al., EMBO J. (1985) 4:1609;and Berg, Proc. Natl. Acad. Sci. USA (1988) 85:99). In addition to theconserved zinc ligand residues, a number of other positions are alsoimportant for the structural integrity of the C2H2 zinc fingers.(Rosenfeld et al., J. Biomol. Struct. Dyn. (1993) 11:557) The bestconserved position, which is generally an aromatic or aliphatic residue,is located four residues after the second cysteine.

Zinc finger, C3HC4 type (RING finger), signature (Zincfing_C3H4; PfamAccession No. PF00097). Some SEQ ID NOS represent polynucleotidesencoding a polypeptide having a C3HC4 type zinc finger signature. Anumber of eukaryotic and viral proteins contain this signature, which isprimarily a conserved cysteine-rich domain of 40 to 60 residues (BordenK. L. B., et al., Curr. Opin. Struct. Biol. (1996) 6:395) that binds twoatoms of zinc, and is probably involved in mediating protein-proteininteractions. The 3D structure of the zinc ligation system is unique tothe RING domain and is refered to as the “cross-brace” motif.

Zinc finger CCHC type (Zincfing_CCHC; Pfam Accession No. PF00098). SomeSEQ ID NOS correspond to genes encoding a member of the family of CCHCzinc fingers. Because the prototype CCHC type zinc finger structure isfrom an HIV protein, this domain is also referred to as aretrovrial-type zinc finger domain. The family also contains proteinsinvolved in eukaryotic gene regulation, such as C. elegans GLH-1. Thestructure is an 18-residue zinc finger; no examples of indels in thealignment. The motif that defines a CCHC type zinc finger domain is:C-X2-C-X4-H-X4-C (Summers J Cell Biochem 1991 January;45(1):41-8). Thedomain is found in, for example, HIV-1 nucleocapsid protein, Moloneymurine leukemia virus nucleocapsid protine NCp10 (De Rocquigny et al.Nucleic Acids Res. (1993) 21:823-9), and myelin transcription factor 1(Myt1) (Kim et al. J. Neurosci. Res. (1997) 50:272-90).

Example 49 Differential Expression of Polynucleotides of the Invention:Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the inventionwas assessed in several libraries prepared from various sources,including cell lines and patient tissue samples. Table 72 provides asummary of these libraries, including the shortened library name (usedhereafter), the mRNA source used to prepared the cDNA library, the“nickname” of the library that is used in the tables below (in quotes),and the approximate number of clones in the library. TABLE 72Description of cDNA Libraries Number of Clones Library in (lib #)Description Library 1 Human Colon Cell Line Km12 L4: High Metastatic308731 Potential (derived from Km12C) 2 Human Colon Cell Line Km12C: LowMetastatic 284771 Potential 3 Human Breast Cancer Cell Line MDA-MB-231:High 326937 Metastatic Potential; micro-mets in lung 4 Human BreastCancer Cell Line MCF7: Non 318979 Metastatic 8 Human Lung Cancer CellLine MV-522: High 223620 Metastatic Potential 9 Human Lung Cancer CellLine UCP-3: Low 312503 Metastatic Potential 12 Human microvascularendothelial cells (HMVEC) - 41938 UNTREATED (PCR (OligodT) cDNA library)13 Human microvascular endothelial cells (HMVEC) - 42100 bFGF TREATED(PCR (OligodT) cDNA library) 14 Human microvascular endothelial cells(HMVEC) - 42825 VEGF TREATED (PCR (OligodT) cDNA library) 15 NormalColon - UC#2 Patient (MICRODISSECTED 282722 PCR (OligodT) cDNA library)16 Colon Tumor - UC#2 Patient (MICRODISSECTED 298831 PCR (OligodT) cDNAlibrary) 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467(MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3Patient (MICRODISSECTED 36216 PCR (OligodT) cDNA library) 19 ColonTumor - UC#3 Patient (MICRODISSECTED 41388 PCR (OligodT) cDNA library)20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956(MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived fromnormal prostate 164801 epithelium 22 WOca Cells derived from GleasonGrade 4 prostate 162088 cancer epithelium 23 Normal Lung Epithelium ofPatient #1006 306198 (MICRODISSECTED PCR (OligodT) cDNA library) 24Primary tumor, Large Cell Carcinoma of Patient 309349 #1006(MICRODISSECTED PCR (OligodT) cDNA library)

The KM12L4, KM12C, and MDA-MB-231 cell lines are described in example 45above. The MCF7 cell line was derived from a pleural effusion of abreast adenocarcinoma and is non-metastatic. The MV-522 cell line isderived from a human lung carcinoma and is of high metastatic potential.The UCP-3 cell line is a low metastatic human lung carcinoma cell line;the MV-522 is a high metastatic variant of UCP-3. These cell lines arewell-recognized in the art as models for the study of human breast andlung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870(MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965(MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586(MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116(MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3);Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki etal., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., AnticancerRes (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997)8:696 (MV522)). The samples of libraries 15-20 are derived from twodifferent patients (UC#2, and UC#3). The bFGF-treated HMVEC wereprepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treatedHMVEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs.Following incubation with the respective growth factor, the cells werewashed and lysis buffer added for RNA preparation. The GRRpz and WOcacell lines were provided by Dr. Donna M. Peehl, Department of Medicine,Stanford University School of Medicine. GRRpz was derived from normalprostate epithelium. The WOca cell line is a Gleason Grade 4 cell line.

Each of the libraries is composed of a collection of cDNA clones that inturn are representative of the mRNAs expressed in the indicated mRNAsource. In order to facilitate the analysis of the millions of sequencesin each library, the sequences were assigned to clusters. The concept of“cluster of clones” is derived from a sorting/grouping of cDNA clonesbased on their hybridization pattern to a panel of roughly 300 7 bpoligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29).Random cDNA clones from a tissue library are hybridized at moderatestringency to 300 7 bp oligonucleotides. Each oligonucleotide has somemeasure of specific hybridization to that specific clone. Thecombination of 300 of these measures of hybridization for 300 probesequals the “hybridization signature” for a specific clone. Clones withsimilar sequence will have similar hybridization signatures. Bydeveloping a sorting/grouping algorithm to analyze these signatures,groups of clones in a library can be identified and brought togethercomputationally. These groups of clones are termed “clusters”. Dependingon the stringency of the selection in the algorithm (similar to thestringency of hybridization in a classic library cDNA screeningprotocol), the “purity” of each cluster can be controlled. For example,artifacts of clustering may occur in computational clustering just asartifacts can occur in “wet-lab” screening of a cDNA library with 400 bpcDNA fragments, at even the highest stringency. The stringency used inthe implementation of cluster herein provides groups of clones that arein general from the same cDNA or closely related cDNAs. Closely relatedclones can be a result of different length clones of the same cDNA,closely related clones from highly related gene families, or splicevariants of the same cDNA.

Differential expression for a selected cluster was assessed by firstdetermining the number of cDNA clones corresponding to the selectedcluster in the first library (Clones in 1^(st)), and the determining thenumber of cDNA clones corresponding to the selected cluster in thesecond library (Clones in 2^(nd)). Differential expression of theselected cluster in the first library relative to the second library isexpressed as a “ratio” of percent expression between the two libraries.In general, the “ratio” is calculated by: 1) calculating the percentexpression of the selected cluster in the first library by dividing thenumber of clones corresponding to a selected cluster in the firstlibrary by the total number of clones analyzed from the first library;2) calculating the percent expression of the selected cluster in thesecond library by dividing the number of clones corresponding to aselected cluster in a second library by the total number of clonesanalyzed from the second library; 3) dividing the calculated percentexpression from the first library by the calculated percent expressionfrom the second library. If the “number of clones” corresponding to aselected cluster in a library is zero, the value is set at 1 to aid incalculation. The formula used in calculating the ratio takes intoaccount the “depth” of each of the libraries being compared, i.e., thetotal number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentiallyexpressed between two samples when the ratio value is greater than atleast about 2, preferably greater than at least about 3, more preferablygreater than at least about 5, where the ratio value is calculated usingthe method described above. The significance of differential expressionis determined using a z score test (Zar, Biostatistical Analysis,Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298(1974).

Examples 50-54 Differential Expression of Polynucleotides of theInvention

A number of polynucleotide sequences have been identified that aredifferentially expressed between, for example, cells derived, from highmetastatic potential cancer tissue and low metastatic cancer cells, andbetween cells derived from metastatic cancer tissue and normal tissue.Evaluation of the levels of expression of the genes corresponding tothese sequences can be valuable in diagnosis, prognosis, and/ortreatment (e.g., to facilitate rationale design of therapy, monitoringduring and after therapy, etc.). Moreover, the genes corresponding todifferentially expressed sequences described herein can be therapeutictargets due to their involvement in regulation (e.g., inhibition orpromotion) of development of, for example, the metastatic phenotype. Forexample, sequences that correspond to genes that are increased inexpression in high metastatic potential cells relative to normal ornon-metastatic tumor cells may encode genes or regulatory sequencesinvolved in processes such as angiogenesis, differentiation, cellreplication, and metastasis.

Detection of the relative expression levels of differentially expressedpolynucleotides described herein can provide valuable information toguide the clinician in the choice of therapy. For example, a patientsample exhibiting an expression level of one or more of thesepolynucleotides that corresponds to a gene that is increased inexpression in metastatic or high metastatic potential cells may warrantmore aggressive treatment for the patient. In contrast, detection ofexpression levels of a polynucleotide sequence that corresponds toexpression levels associated with that of low metastatic potential cellsmay warrant a more positive prognosis than the gross pathology wouldsuggest.

A number of polynucleotide sequences of the present invention aredifferentially expressed between human microvascular endothelial cells(HMVEC) that have been treated with growth factors relative to untreatedHMVEC. Sequences that are differentially expressed between growthfactor-treated HMVEC and untreated HMVEC can represent sequencesencoding gene products involved in angiogenesis, metastasis (cellmigration), and other development and oncogenic processes. For example,sequences that are more highly expressed in HMVEC treated with growthfactors (such as bFGF or VEGF) relative to untreated HMVEC can serve asdrug targets for chemotherapeutics, e.g., decreasing expression of suchup-regulated genes or inhibiting the activity of the encoded geneproduct would serve to inhibit tumor cell angiogenesis. Detection ofexpression of these sequences in colon cancer tissue can be valuable indetermining diagnostic, prognostic and/or treatment informationassociated with the prevention of achieving the malignant state in thesetissues, and can be important in risk assessment for a patient. Apatient sample displaying an increased level of one or more of thesepolynucleotides may thus warrant closer attention or more frequentscreening procedures to catch the malignant state as early as possible.

The differential expression of the polynucleotides described herein canthus be used as, for example, diagnostic markers, prognostic markers,for risk assessment, patient treatment and the like. Thesepolynucleotide sequences can also be used in combination with otherknown molecular and/or biochemical markers. The following examplesprovide relative expression levels of polynucleotides from specifiedcell lines and patient tissue samples.

Example 50 High Metastatic Potential Breast Cancer Versus Low MetastaticBreast Cancer Cells

The tables bellow summarize the data for polynucleotides that representgenes differentially expressed between high metastatic potential and lowmetastatic potential breast cancer cells. TABLE 73 High metastaticpotential breast (lib3) > low metastatic potential breast cancer cells(lib4) SEQ ID NO: Lib 3 Clones Lib4 Clones Lib3/Lib4 9621 13 0 12.689618 9 0 8.78 9596 8 0 7.81 9619 7 0 6.83 9531 7 0 6.83 9526 7 0 6.839756 6 0 5.85

TABLE 74 Low metastatic potential breast (lib4) > high metastaticpotential breast cancer cells (lib3) SEQ ID NO: Lib 3 Clones Lib4 ClonesLib4/Lib3 9398 0 340 348.48 9496 0 64 65.6 9501 0 57 58.42 9487 0 4344.07 9387 0 41 42.02 9488 0 40 41 9432 4 115 29.47 9494 0 28 28.7 94860 21 21.52 9476 3 61 20.84 9373 1 17 17.42 9389 0 17 17.42 9490 3 5017.08 9429 0 16 16.4 8950 0 16 16.4 9497 0 16 16.4 9464 0 16 16.4 9477 013 13.32 9376 0 12 12.3 9493 1 11 11.27 9402 1 11 11.27 9427 1 11 11.279449 1 11 11.27 9430 0 10 10.25 9481 0 10 10.25 9372 1 10 10.25 9463 0 99.22 9431 0 8 8.2 9361 0 8 8.2 9054 0 7 7.17 9447 0 7 7.17 9394 0 7 7.179395 0 7 7.17 9422 0 7 7.17 9424 0 7 7.17 9439 0 7 7.17 9401 0 6 6.159412 0 6 6.15 9199 0 6 6.15 9475 0 6 6.15 8953 0 6 6.15 9443 0 6 6.15

Example 51 High Metastatic Potential Lung Cancer Versus Low MetastaticLung Cancer Cells

The following summarizes polynucleotides that represent genesdifferentially expressed between high metastatic potential lung cancercells and low metastatic potential lung cancer cells: TABLE 75 Highmetastatic potential lung (lib8) > low metastatic potential lung cancercells (lib9) SEQ ID NO: Lib 8 Clones Lib 9 Clones Lib8/Lib9 9411 35 148.91 9809 8 0 11.18 9190 5 0 6.99

Example 52 High Metastatic Potential Colon Cancer Versus Low MetastaticColon Cancer Cells

Table 76 summarizes polynucleotides that represent genes differentiallyexpressed between high metastatic potential and low metastatic potentialcolon cancer cells: TABLE 76 Low metastatic potential colon (lib2) >high metastatic potential colon cancer cells (lib1) SEQ ID NO: Lib1Clones Lib2 Clones Lib2/Lib1 8897 0 8 8.67 8943 0 6 6.5 9029 0 6 6.5

Example 53 High Tumor Potential Colon Tissue Vs. Metastasized ColonCancer Tissue

The following table summarizes polynucleotides that represent genesdifferentially expressed between high tumor potential colon cancer cellsand cells derived from high metastatic potential colon cancer cells of apatient. TABLE 77 High tumor potential colon tissue (lib16) vs. highmetastatic colon tissue (lib17) SEQ ID NO: Lib 16 Lib 17 Lib17/Lib168940 0 7 6.89 9210 3 12 3.94

Example 54 Differential Expression Across Multiple Libraries

A number of polynucleotide sequences have been identified that representgenes that are differentially expressed across multiple libraries.Expression of these sequences in a tissue or any origin can be valuablein determining diagnostic, prognostic and/or treatment informationassociated with the prevention of achieving the malignant state in thesetissues, and can be important in risk assessment for a patient. Thesepolynucleotides can also serve as non-tissue specific markers of, forexample, risk of metastasis of a tumor. The differential expression datafor these sequences is provided in Table 78 below. TABLE 78 GenesDifferentially Expressed Across Multiple Library Comparisons SEQ ID NO:Cell or Tissue Sample and Cancer State Compared RATIO 8874 Low Met Colon(lib2) > High Met Colon (lib1) 8.67 8874 High Met Breast (lib3) > LowMet Breast (Lib4) 5.85 9049 Low Met Lung (lib9) > High Met Lung (lib8)17.44 9049 Colon Tumor Tissue (lib16) > Normal Colon 3.42 Tissue (lib15)9049 Colon Tumor Tissue (lib19) > Normal Colon 66.5 Tissue (lib18) 9049High Met Colon Tissue (lib20) > Normal Colon 14.04 Tissue (lib18) 9049Colon Tumor Tissue (lib19) > High Met Colon 4.74 Tissue (lib20) 9156High Met Colon (lib1) > Low Met Colon (lib2) 5.76 9156 Low Met Breast(lib4) > High Met Breast (Lib3) 17.28 9485 Low Met Breast (lib4) > HighMet Breast (Lib3) 6.15 9485 High Met Lung (lib8) > Low Met Lung (lib9)19.56 9694 High Met Breast (lib3) > Low Met Breast (Lib4) 9.76 9694HMVEC-bFGF (lib13) > HMVEC (lib12) 4.98 9694 Lung Tumor Tissue (lib24) >Normal Lung Tissue 5.94 (lib23)Key for Table 78:High Met = high metastatic potential;Low Met = low metastatic potential;met = metastasized;tumor = non-metastasized tumor;HMVEC = human microvascular endothelial cell;bFGF = bFGF treated.

Detection of expression of genes that correspond to the abovepolynucleotides may be of particular interest in diagnosis, prognosis,risk assesment, and monitoring of treatment. Furthermore, differentialexpression of a specific gene across multiple libraries can also beindicative of a gene whose expression is associated with, for example,suppression of the metastatic phenotype or with development of the celltoward a metastatic phenotype. For example, SEQ ID NO:9012 correspondsto a gene that is expressed at relatively higher levels in colon tumortissue than in high metastatic potential colon tumor tissue, and atrelatively higher levels in high metastatic potential colon tumor tissuethan in normal colon tissue. Thus a relatively increased level ofexpression of the gene corresponding to SEQ ID NO:9012 may be used asmarker of a pre-metastatic colon cells either alone or in combinationwith other markers.

Some polynucleotides exhibited opposite differential expression trendsin libraries of different origin (see, e.g., SEQ ID NO:9119). These datasuggest that the differential expressio patterns of some gene associatedwith development of metastases indicate a unique role for those genesspecific for the tissue of origin.

Those skilled in the art will recognize, or be able to ascertain, usingnot more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such specific embodimentsand equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Deposit Information. The following materials were deposited with theAmerican Type Culture Collection (CMCC=Chiron Master CultureCollection). TABLE 79 Cell Lines Deposited Deposited with ATCC CMCC CellLine Deposit Date ATCC Accession No. Accession No. KM12L4-A Mar. 19,1998 CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May15, 1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containingspecific clones, were assigned an “ES” number (internal reference) anddeposited with the ATCC. Table 80 below provides the ATCC Accession Nos.of the ES deposits, all of which were deposited on or before May 13,1999. The names of the clones contained within each of these depositsare provided in the tables 81 and 82. TABLE 80 Pools of Clones andLibraries Deposited with ATCC on or before Sep. 23, 1999 Library No.CMCC No. ATCC Deposit No. ES55 5058 PTA-739 ES56 5059 PTA-740 ES57 5060PTA-741 ES58 5061 PTA-742 ES59 5062 PTA-743 ES60 5063 PTA-744 ES61 5064PTA-745 ES62 5065 PTA-746 ES63 5066 PTA-747 ES64 5067 PTA-748 ES65 5068PTA-749 ES66 5069 PTA-750 ES67 5070 PTA-751 ES68 5071 PTA-752 ES69 5072PTA-753 ES70 5073 PTA-754 ES71 5074 PTA-755 ES72 5075 PTA-756 ES73 5076PTA-757 ES74 5077 PTA-758

TABLE 81 ES55 ES56 ES57 ES58 M00004170C:H06 M00004036B:C11M00004288D:E07 M00023298B:G07 M00004170D:C06 M00004064B:G03M00004318D:D07 M00026819B:E02 M00004171D:H10 M00004067C:E05M00004356C:D02 M00026914C:H10 M00004174B:B12 M00004099C:F04M00004391C:F12 M00027023B:H12 M00004175D:G10 M00004103A:E06M00004386C:C03 M00027085A:G10 M00004176A:E07 M00004128B:H11M00004414D:C11 M00027248D:D01 M00001352D:A09 M00004167A:H04M00004422C:A01 M00027546B:A11 M00001345C:B10 M00004158C:B01M00004427D:H04 M00023299B:A01 M00001382D:F03 M00004165B:E03M00004502B:G05 M00026857A:F02 M00001419A:E01 M00004181A:B05M00004495D:A05 M00026858C:H05 M00001437D:A12 M00003993C:G11M00005364C:A02 M00026861A:B05 M00001441D:G02 M00004046C:A04M00005375B:H03 M00026846C:B01 M00001601D:A03 M00004034A:G03M00005420C:E10 M00027131A:H02 M00001677B:G01 M00004036C:E10M00005413B:B02 M00027396A:F07 M00001678A:B10 M00004043C:A06M00005438D:A08 M00023301B:C01 M00001675C:F05 M00004067C:C10M00005453B:B06 M00023321B:F06 M00001360D:C12 M00004068A:A03M00005446B:D10 M00023401C:D12 M00001389C:E01 M00004069A:E04M00005493D:H12 M00026941C:E11 M00001390C:H05 M00004071C:B06M00005476D:A11 M00027067A:B02 M00001399B:C04 M00004127C:C08M00005482A:D08 M00027036B:D07 M00001507A:H06 M00004157C:E06M00005485C:F09 M00027329A:H04 M00003747C:G12 M00004165D:H12M00005563C:D05 M00027740C:C05 M00001358B:F12 M00003995B:C06M00005569B:E04 M00023340A:A10 M00001360B:F09 M00004090A:B11M00005621B:C09 M00026942C:A06 M00001392A:F02 M00004084C:F05M00005628D:A10 M00027066A:A04 M00001397D:G04 M00004087A:H06M00005629B:G06 M00027072C:A11 M00001463C:E12 M00004110A:G03M00004866C:H08 M00027028A:B06 M00001531B:A03 M00004117D:F06M00004872C:G03 M00023282B:H09 M00001507D:F09 M00004150A:B09M00005358B:D10 M00023295B:C03 M00001513B:F05 M00004140C:D04M00005385D:B08 M00026811A:H01 M00001514B:C02 M00004175D:D05M00005392C:B03 M00026850B:F07 M00001576C:E03 M00004176A:H05M00005395C:C11 M00026913D:G11 M00003756D:B09 M00004170C:A12M00005396A:C01 M00026936D:D01 M00003907C:D02 M00004237B:G01M00005435B:F01 M00027083C:F06 M00003926A:D01 M00004253A:E02M00005464B:B08 M00027152D:H06 M00003928D:A04 M00003997D:G03M00005505B:D10 M00027209D:B09 M00003935D:E04 M00003998C:D04M00005509D:G05 M00027339D:E10 M00003985B:F06 M00004027C:E06M00005614A:B07 M00027282D:G01 M00004063B:B12 M00004059D:A09M00005721C:A12 M00023287A:D08 M00004101A:C12 M00004087B:D05M00005705D:G09 M00026928A:B06 M00004104C:F06 M00004114C:B09M00005709D:H05 M00027028B:C12 M00004107A:E02 M00004140B:C02M00004859D:D01 M00027115B:G04 M00004108B:D04 M00004149C:D11M00005342D:E04 M00027096B:A01 M00003856A:H10 M00004168D:F05M00005363D:C05 M00027154B:D05 M00003908C:C04 M00004176B:H09M00005353C:H01 M00027164A:A09 M00003895C:F05 M00004173A:D03M00005386C:G01 M00027218C:D06 M00003939B:C02 M00004209B:G01M00005388B:B02 M00023343B:C08 M00003997A:C08 M00004253D:D04M00005396C:H04 M00026871C:F12 M00004066D:C02 M00004275A:H07M00005434A:F11 M00026882A:E07 M00004105C:C05 M00004269C:B10M00005434C:E02 M00027067B:E09 M00003788B:C08 M00004298A:H09M00005473C:F02 M00027062C:C04 M00003788C:C05 M00004347A:F10M00005459B:A01 M00027131C:E07 M00003835B:C05 M00004337A:A07M00005469A:D10 M00027137D:F05 M00003820B:G04 M00004372A:A08M00005505D:H08 M00027204B:A08 M00003888C:G08 M00004406D:E11M00005509B:E10 M00027188A:D12 M00003977D:H04 M00004449B:B05M00005616B:E11 M00027190B:F06 M00004029D:H03 M00004507A:F11M00005589B:H12 M00027193A:F07 M00004034A:A05 M00004276A:C06M00005721D:B03 M00022362D:G11 M00004140D:E03 M00004270C:H05M00005698A:H12 M00007947B:F07 M00003775C:C01 M00004343A:G07M00006613C:C02 M00007948B:B07 M00003776B:F08 M00004344B:C06M00006617A:A06 M00008003B:F09 M00003839D:C03 M00004373D:G10M00006584D:D01 M00008054C:C03 M00003818C:D02 M00004368A:G11M00006594B:D05 M00008075D:B01 M00003820C:E08 M00004371B:A05M00006600D:G07 M00022074A:F05 M00003822A:D02 M00004403A:A02M00006631D:G09 M00007943C:B02 M00003877C:G01 M00004445D:A04M00006635A:C01 M00008002B:F09 M00003880A:G10 M00004447A:A10M00006726D:H10 M00021653C:B06 M00003919D:F01 M00004603D:D09M00006874D:E01 M00021851D:H06 M00003960D:E09 M00004326D:D06M00006882C:D03 M00022015D:C11 M00004081A:E11 M00004323B:G12M00006925B:B02 M00022018B:E09 M00004085B:D12 M00004350A:C04M00006946B:C08 M00022095C:F03 M00004142C:A06 M00004357A:B10M00006949B:C07 M00007996C:B11 M00004135D:D01 M00004360B:B08M00007026A:A03 M00007977B:C11 M00004198B:G08 M00004385D:D06M00006712A:F01 M00008088D:B01 M00004185B:H03 M00004414D:A01M00006727A:H12 M00021676B:B12 M00004187A:B05 M00004415A:A01M00006815D:D11 M00021972A:C10 M00004251B:H12 M00004423A:B05M00006805D:H12 M00022099C:A10 M00004232D:G11 M00004423C:F03M00006934B:B11 M00022106D:B06 M00004240A:D03 M00004426B:H06M00007019B:G01 M00007978B:C04 M00004285C:B06 M00004504C:G07M00007038D:D01 M00008053D:E09 M00004292A:C08 M00004466A:E04M00007041C:C05 M00021669B:G02 M00004335A:G05 M00004498D:A11M00006630A:E05 M00022118A:D08 M00004240C:A06 M00004292A:F03M00006623C:G07 M00022251A:F07 M00004249A:C09 M00004280D:D10M00006694D:G06 M00022235D:F07 M00004335D:D03 M00004286D:D02M00006668D:B10 M00022240C:B03 M00004378A:H10 M00004870D:E05M00006688A:F09 M00022406C:G03 M00004381A:E10 M00004871C:C04M00006745B:C05 M00022459C:G05 M00004444C:H11 M00004872A:D07M00006846A:B03 M00022627B:D01 M00004225A:E03 M00005395D:D11M00006823A:H06 M00022184D:F07 M00004284A:C09 M00005395D:B12M00006925A:B09 M00022177D:G02 M00004264B:F03 M00005412D:G07M00006894D:A07 M00022460C:E12 M00004404C:B03 M00005413D:G12M00006895D:A02 M00022627A:A02 M00004410A:F06 M00005513A:H01M00006991B:E05 M00022144D:D09 M00004412A:G05 M00005515D:G02M00006994A:C12 M00022203B:A05 M00001340C:A08 M00005607A:C08M00007046D:E10 M00022214C:C11 M00001340C:D09 M00005366D:E12M00006577A:B01 M00022252C:A04 M00001395D:B04 M00005618C:H11M00006630A:E09 M00022420B:C08 M00001466C:H11 M00005708C:D11M00006619A:G11 M00022640B:G10 M00001528D:B12 M00005810B:C07M00006704A:C11 M00022641C:H03 M00001517C:A10 M00006795C:B12M00022127C:E01 M00022652B:G06 M00001561A:G10 M00006755C:C03M00022128A:C05 M00022216C:H02 M00001565C:F06 M00006756D:G07M00022176D:F05 M00022199A:F09 M00001569A:H01 M00006779D:F03M00022214A:H05 M00022214A:D01 M00001341A:H10 M00004821D:C03M00022220B:B06 M00022273A:B03 M00001375C:C11 M00005358A:H03M00022278C:E04 M00022256D:G11 M00001397C:F01 M00005480C:A04M00022282A:A11 M00022261C:D06 M00001431A:F03 M00005481C:H05M00022260C:H07 M00022490B:G12 M00001457D:E08 M00005490B:B02M00022263A:C01 M00022648D:G11 M00001505C:C10 M00005820A:H11M00022377A:E02 M00022709A:G02 M00001615A:D01 M00006621B:B06M00022399C:B02 M00022701C:A05 M00001618C:E01 M00006752C:D04M00022056C:D12 M00022826A:C08 M00001358C:D09 M00006757D:H04M00022087A:D01 M00022963A:E07 M00001360B:B01 M00005000A:H05M00022088B:E05 M00022904D:D04 M00001391C:B05 M00005296D:G03M00022090D:B03 M00023095C:A09 M00001389B:B12 M00005378B:B04M00022094A:A09 M00022684C:C12 M00001485A:C04 M00005461C:D11M00022096B:D10 M00022765B:E03 M00001559D:E02 M00005464D:D07M00022176A:F02 M00022898C:H07 M00001545D:F12 M00005657B:F11M00022217B:E03 M00022902B:F10 M00001549C:F10 M00006596D:H02M00022259A:D04 M00023003A:H01 M00001579C:E07 M00005826B:F10M00022381B:C12 M00022768A:A10 M00001630A:E08 M00006577B:F01M00022399D:A07 M00022834A:H02 M00001386B:E01 M00006582A:F12M00022401C:G07 M00023002A:C02 M00001389A:F03 M00006664A:C05M00022407D:G07 M00023003C:C10 M00001418C:F06 M00006678C:B07M00022417B:C01 M00023012A:C06 M00001454D:H09 M00006840A:A12M00022435C:C05 M00007973D:B03 M00001442D:D09 M00005020B:D10M00022471D:A05 M00007939A:F06 M00001450D:H12 M00005296B:H07M00022464D:F12 M00007941D:D07 M00001479D:B10 M00005403A:D12M00022469A:A05 M00007948D:F08 M00001598C:F02 M00005376B:E08M00022500B:D01 M00008012D:H04 M00001594A:H01 M00005378C:B12M00022506D:B03 M00008014D:A11 M00001657D:D07 M00005397A:G08M00022542A:B06 M00008048C:A08 M00003772C:F12 M00005449D:D04M00022527D:A09 M00008099A:C12 M00003844D:B02 M00005465A:A07M00022568B:D03 M00021668D:G09 M00003845B:A04 M00005648C:C11M00022561D:E06 M00021861C:B08 M00003845C:F08 M00006595C:B08M00022687C:C11 M00021980A:F03 M00003848A:E08 M00006816D:D08M00022695D:B02 M00007931A:B07 M00003880C:D06 M00006835D:C08M00022425A:F11 M00007948C:G01 M00001647D:A02 M00006914C:D07M00022434D:B06 M00007969B:E10 M00001655C:F07 M00007177A:G07M00022460D:C07 M00008012B:C05 M00003804D:F12 M00006920B:H07M00022510A:B09 M00008012D:E07 M00003884C:G09 M00007161C:D12M00022501D:A09 M00008014C:H01 M00003916D:A10 M00006968D:H02M00022541D:G06 M00008016C:E06 M00003943B:C12 M00006936C:G11M00022527B:H05 M00008052C:G11 M00003935A:C04 M00006945D:A07M00022538D:B02 M00008054C:E07 M00003937D:F09 M00007047C:H04M00022559D:F10 M00008093C:G08 M00001683B:F12 M00007065D:A03M00022569D:H03 M00021614A:C09 M00001669B:H04 M00007079D:H01M00022601A:A09 M00008094D:C02 M00003762D:C02 M00006968A:H05M00022604A:F06 M00021667C:G10 M00003788D:E06 M00007078B:H04M00022684B:F11 M00021674A:B07 M00003824A:B11 M00007186A:A12M00022702A:D10 M00021846B:F05 M00003865B:D10 M00004852B:H08M00022691A:G01 M00021847B:A09 M00003870C:H03 M00005382A:G09M00022696A:H03 M00021963C:H04 M00003901B:C02 M00005418C:B09M00022444B:C04 M00007985C:G07 M00003893A:D03 M00005420C:E03M00022447A:H06 M00008001D:F11 M00003931A:G01 M00005450C:G09M00022488C:H02 M00007992A:G04 M00003973A:D09 M00005444D:D01M00022522B:A05 M00008000D:B06 M00001660A:B10 M00005494C:F08M00022513C:G04 M00008001A:G11 M00003761C:C05 M00005479C:A05M00022517C:B01 M00008044C:A05 M00003829C:G07 M00005486A:F07M00022546B:F12 M00008085B:G01 M00003833D:F11 M00005538C:H11M00022591C:F03 M00008082B:C05 M00003879D:A09 M00005648C:E10M00022617B:A01 M00008083A:H11 M00003880B:B08 M00005621A:B05M00022681D:H10 M00021624B:E11 M00003861D:G10 M00004847D:G01M00022659B:C01 M00021689A:G05 M00003876C:G11 M00005342B:G01M00022664C:G10 M00021865B:F06 M00003877C:C11 M00005305A:H01M00022711B:A05 M00021879B:C11 M00003902C:D02 M00026906B:G03M00022704A:H08 M00021958A:A03 M00003933A:B04 M00026872A:C10M00022449D:B05 M00021945A:B04 M00003923D:A03 M00026964C:H02M00022548A:F02 M00021981D:A11 M00003989D:A02 M00026982C:D08M00022590D:E08 M00007987A:D10 M00003991A:D05 M00027069D:F02M00022622A:E08 M00007998C:B04 M00004030C:E05 M00027042D:E02M00022655A:F09 M00008001B:E11 M00004048A:E10 M00027056B:H07M00022664A:E04 M00008045A:B05 M00006680D:A01 M00027137C:A03M00022720A:C01 M00008023A:B03 M00006688C:C12 M00027184D:H02M00022722D:C07 M00008027D:H09 M00006740A:A06 M00027189C:D04M00022746D:D05 M00008044B:F07 M00006757A:C09 M00027196A:A10M00022772A:A06 M00008089C:B08 M00006859D:E11 M00027357D:A02M00022813C:B09 M00021620D:B06 M00006917B:C05 M00027369A:B03M00022853D:C05 M00021624B:D03 M00006919A:H12 M00027439B:A09M00022843A:D02 M00021628C:B09 M00006993B:F02 M00027393D:F01M00022844C:A01 M00021680D:H08 M00007093C:C11 M00027557D:B06M00022968D:G06 M00021687C:A04 M00007047D:C02 M00027502C:H02M00023023B:A05 M00021696C:E02 M00007064B:E09 M00027507C:C06M00022716A:C01 M00021698A:H03 M00007121A:G04 M00027529B:B11M00022725D:G05 M00021864C:C07 M00007107C:D02 M00027438D:A03M00022817D:B09 M00021958A:A04 M00007178D:A10 M00027388A:G05M00022848D:H09 M00021949D:A05 M00007156D:E11 M00027396C:B06M00022884D:A07 M00021951B:A01 M00007172D:H03 M00027551C:B07M00022983A:H04 M00022001B:H10 M00007175D:G02 M00027518B:B07M00023034B:B10 M00022001D:E06 M00007121D:A11 M00027528A:G03M00023038D:D04 M00022071D:C08 M00007101C:H01 M00027759B:E11M00022743C:G05 M00022078B:B04 M00007104D:D10 M00027728A:B03M00022734C:A03 M00022113B:A12 M00007116A:C08 M00027484A:G03M00022737D:B02 M00022138C:B07 M00007152A:A10 M00027752B:E05M00022801A:G04 M00022152A:G05 M00007179B:H04 M00022838B:E05M00022158C:C08 M00007157B:B04 M00022856A:B09 M00022192B:H07M00007167C:B10 M00022902C:F11 M00022233C:D11 M00007175B:B11M00022893D:C06 M00022252A:C01 M00007177B:C02 M00022922D:G06M00022370A:G07 M00007141A:G08 M00022986B:C02 M00022300A:A05M00007196D:D02 M00023002D:C12 M00022386D:C04 M00007145C:B05M00023096C:A03 M00022072D:E12 M00007126D:H01 M00023097A:C03M00022102D:A10 M00007140C:G12 M00022743C:G06 M00022207C:C01M00007200A:B12 M00022736B:B03 M00022249C:G09 M00007203C:E06M00022737B:F12 M00022383C:F05 M00022831C:F11 M00022384B:E06M00022836C:A07 M00022067A:B03 M00022854D:C04 M00022056B:G12M00022860A:A07 M00022084B:C03 M00022861C:B04 M00022087D:F12M00023096A:F03 M00023096D:B11 M00023097C:D10

TABLE 82 ES59 ES60 ES61 ES62 M00001418A:A02 M00001477A:G02M00004450A:G07 M00005515B:B08 M00003877C:A08 M00003853C:A09M00004353D:C06 M00005385B:A10 M00003977C:D01 M00001694B:H12M00004406A:H12 M00005516D:F12 M00004295A:C02 M00001664D:E02M00004048C:C02 M00005822D:C05 M00001383C:C04 M00003847B:H01M00004170B:G04 M00004841C:H03 M00001500A:A02 M00001631D:G08M00004108C:D07 M00005810B:G02 M00003880B:D03 M00004498D:F02M00004125B:A02 M00007107A:H08 M00003803B:G12 M00001563A:F04M00004109A:B07 M00004825A:G12 M00003819D:B02 M00001558D:E02M00004123B:G05 M00005327C:G08 M00004178B:F07 M00004278C:H11M00004152A:F03 M00005390C:E05 ES63 ES64 ES65 ES66 M00005520A:H11M00006790D:F10 M00027175D:A05 M00026949A:F04 M00006814D:D09M00006627C:C02 M00026910C:C05 M00023432D:F09 M00006918D:G08M00027462D:A12 M00027280D:H01 M00027178B:E04 M00007197D:D12M00026972A:F04 M00023289D:E06 M00027225B:D03 M00005497C:G08M00027592D:C05 M00023373A:D01 M00023340B:B07 M00007109D:G01M00026945B:C10 M00027231A:D01 M00027283C:H12 M00005377C:F07M00027231C:D08 M00023321A:F07 M00027085C:H12 M00006813B:E04M00027083D:F06 M00027266C:G12 M00027234C:B05 M00005825A:A10M00027142A:C01 M00023398D:F10 M00023390A:C04 M00005416B:A01M00027607A:A09 M00027603C:E02 M00026810A:H04 ES67 ES68 ES69 ES70M00023340B:H12 M00027642C:D11 M00022714B:D04 M00022709A:C01M00027237C:D04 M00027202B:B09 M00022838A:H05 M00022413B:D07M00026809C:D10 M00027459A:G12 M00022392C:H06 M00022467C:H07M00027386D:C02 M00027250A:C04 M00022363C:D03 M00022561B:B09M00027343B:H05 M00027499B:G02 M00022205A:C02 M00022214C:E09M00027356A:H02 M00027053C:B06 M00022717C:F05 M00022697A:C08M00027363D:A08 M00027598C:D06 M00008015B:D08 M00022682A:F10M00027364D:E08 M00006989C:B01 M00021625B:G07 M00021841A:E11M00027618A:B08 M00006837B:H12 M00008100D:C08 M00021691B:E04M00027628D:D08 M00007202A:A09 M00022669D:G07 M00022477C:C07 ES71 ES72ES73 ES74 M00022134D:D12 M00008028D:B01 M00022513C:E10 M00023363C:A04M00022705B:F08 M00021931B:F04 M00022518C:C04 M00001401B:A02M00022903D:H02 M00008097C:E04 M00022544C:D08 M00008023C:A06M00022915C:C09 M00008082B:H10 M00022785C:B10 M00022077D:A12M00007965C:B02 M00008006A:H02 M00022525C:E09 M00023284B:G06M00022368C:C11 M00022167B:H02 M00022641D:F08 M00023369D:C05M00007937C:E08 M00022509D:A12 M00022923A:A09 M00023413D:F04M00021852C:D12 M00022169A:E11 M00026905A:G11 M00008000D:G11M00022184D:H07 M00027169D:H06 M00021908B:F03 M00022441B:A06M00005434D:H02

The deposits described herein are provided merely as convenience tothose of skill in the art, and is not an admission that a deposit isrequired under 35 U.S.C. §112. The sequence of the polynucleotidescontained within the deposited material, as well as the amino acidsequence of the polypeptides encoded thereby, are incorporated herein byreference and are controlling in the event of any conflict with thewritten description of sequences herein. A license may be required tomake, use, or sell the deposited material, and no such license isgranted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones. Where theATCC deposit is composed of a pool of cDNA clones or a library of cDNAclones, the deposit was prepared by first transfecting each of theclones into separate bacterial cells. The clones in the pool or librarywere then deposited as a pool of equal mixtures in the compositedeposit. Particular clones can be obtained from the composite depositusing methods well known in the art. For example, a bacterial cellcontaining a particular clone can be identified by isolating singlecolonies, and identifying colonies containing the specific clone throughstandard colony hybridization techniques, using an oligonucleotide probeor probes designed to specifically hybridize to a sequence of the cloneinsert (e.g., a probe based upon unmasked sequence of the encodedpolynucleotide having the indicated SEQ ID NO). The probe should bedesigned to have a T_(m) of approximately 80° C. (assuming 2° C. foreach A or T and 4° C. for each G or C). Positive colonies can then bepicked, grown in culture, and the recombinant clone isolated.Alternatively, probes designed in this manner can be used to PCR toisolate a nucleic acid molecule from the pooled clones according tomethods well known in the art, e.g., by purifying the cDNA from thedeposited culture pool, and using the probes in PCR reactions to producean amplified product having the corresponding desired polynucleotidesequence.

Example 55 Source of Biological Materials and Overview of NovelPolynucleotides Expressed by the Biological Materials

Cell lines and human normal and tumor tissue were used to construct cDNAlibraries from mRNA isolated from the cells and tissues. Most sequenceswere about 275-300 nucleotides in length. The cells lines includeKm12L4-A cell line, a high metastatic colon cancer cell line (Morika, W.A. K. et al., Cancer Research (1988) 48:6863). The KM12L4-A cell line isderived from the KM12C cell line. The KM12C cell line, which is poorlymetastatic (low metastatic) was established in culture from a Dukes'stage B2 surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863).The KML4-A is a highly metastatic subline derived from KM12C (Yeatman etal. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet.Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM 12C-derivedcell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the artas model cell lines for the study of colon cancer (see, e.g., Moriakawaet al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman etal., (1995) supra; Yeatman et al., Clin. Exp. Metastasis (1996) 14:246).These and other cell lines and tissue are described in Table 88.

The sequences of the isolated polynucleotides were first masked toeliminate low complexity sequences using the XBLAST masking program(Claverie “Effective Large-Scale. Sequence Similarity Searches,” In:Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed.,Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); seeparticularly Claverie, in “Automated DNA Sequencing and AnalysisTechniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, SanDiego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally,masking does not influence the final search results, except to eliminatesequences of relative little interest due to their low complexity, andto eliminate multiple “hits” based on similarity to repetitive regionscommon to multiple sequences, e.g., Alu repeats. The sequences remainingafter masking were then used in a BLASTN vs. Genbank search; sequencesthat exhibited greater than 70% overlap, 99% identity, and a p value ofless than 1×10⁻⁴⁰ were discarded. Sequences from this search also werediscarded if the inclusive parameters were met, but the sequence wasribosomal or vector-derived.

The resulting sequences from the previous search were classified intothree groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP(non-redundant proteins) database search: (1) unknown (no hits in theGenbank search), (2) weak similarity (greater than 45% identity and pvalue of less than 1×10⁻⁵), and (3) high similarity (greater than 60%overlap, greater than 80% identity, and p value less than 1×10⁻⁵).Sequences having greater than 70% overlap, greater than 99% identity,and p value of less than 1×10⁻⁴⁰ were discarded.

The remaining sequences were classified as unknown (no hits), weaksimilarity, and high similarity (parameters as above). Two searches wereperformed on these sequences. First, a BLAST vs. EST database search wasperformed and sequences with greater than 99% overlap, greater than 99%similarity and a p value of less than 1×10⁻⁴⁰ were discarded. Sequenceswith a p value of less than 1×10⁻⁶⁵ when compared to a database sequenceof human origin were also excluded. Second, a BLASTN vs. Patent GeneSeqdatabase was performed and sequences having greater than 99% identity, pvalueless than 1×10⁻⁴⁰, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rulesand redundancies in the dataset. Sequences with a p value of less than1×10⁻¹¹¹ in relation to a database sequence of human origin werespecifically excluded. The final result provided the 3351 sequenceslisted in the accompanying Sequence Listing. Each identifiedpolynucleotide represents sequence from at least a partial mRNAtranscript. Polynucleotides that were determined to be novel wereassigned a sequence identification number.

The novel polynucleotides were assigned sequence identification numbersSEQ ID NOs:9920-12191. The DNA sequences corresponding to the novelpolynucleotides are provided in the Sequence Listing. Tables 83 and 84and 2 provide: 1) the SEQ ID NO assigned to each sequence for use in thepresent specification or a corresponding number; 2) the sequence nameused as an internal identifier of the sequence; 3) the name assigned tothe clone from which the sequence was isolated; and 4) the number of thecluster to which the sequence is assigned (Cluster ID; where the clusterID is 0, the sequence was not assigned to any cluster).

Because the provided polynucleotides represent partial mRNA transcripts,two or more polynucleotides of the invention may represent differentregions of the same mRNA transcript and the same gene. Thus, if two ormore SEQ ID NOs: are identified as belonging to the same clone, theneither sequence can be used to obtain the full-length mRNA or gene.

Example 56 Results of Public Database Search to Identify Function ofGene Products

SEQ ID NOs:9920-13270 were translated in all three reading frames todetermine the best alignment with the individual sequences. These aminoacid sequences and nucleotide sequences are referred to, generally, asquery sequences, which are aligned with the individual sequences. Queryand individual sequences were aligned using the BLAST programs,available over the world wide web at http://www.ncbi.nlm.nih.gov/BLAST/.Again the sequences were masked to various extents to prevent searchingof repetitive sequences or poly-A sequences, using the XBLAST programfor masking low complexity as described above.

Tables 85 and 86 (inserted before the claims) show the results of thealignments. Tables 85 and 86 refer to each sequence by its SEQ ID NO ora corresponding number, the accession numbers and descriptions ofnearest neighbors from the Genbank and Non-Redundant Protein searches,and the p values of the search results.

The activity of the polypeptide encoded by SEQ ID NOs:9920-13270 is thesame or similar to the nearest neighbor reported in Table 85 or 86. Theaccession number of the nearest neighbor is reported, providing areference to the activities exhibited by the nearest neighbor. Thesearch program and database used for the alignment also are indicated aswell as a calculation of the p value.

Full length sequences or fragments of the polynucleotide sequences ofthe nearest neighbors can be used as probes and primers to identify andisolate the full length sequence of SEQ ID NOs: 9920-13270. The nearestneighbors can indicate a tissue or cell type to be used to construct alibrary for the full-length sequences of SEQ ID NOs: 9920-132701.

Example 57 Members of Protein Families

The sequences were used to conduct a profile search as described in thespecification above. Several of the polynucleotides of the inventionwere found to encode polypeptides having characteristics of apolypeptide belonging to a known protein families (and thus representnew members of these protein families) and/or comprising a knownfunctional domain (Table 87). “Start” and “stop” in Table 3 indicate theposition within the individual sequences that align with the querysequence having the indicated SEQ ID NO. The direction indicates theorientation of the query sequence with respect to the individualsequence, where forward (for) indicates that the alignment is in thesame direction (left to right) as the sequence provided in the SequenceListing and reverse (rev) indicates that the alignment is with asequence complementary to the sequence provided in the Sequence Listing.

Some polynucleotides exhibited multiple profile hits because, forexample, the particular sequence contains overlapping profile regions,and/or the sequence contains two different functional domains. Theseprofile hits are described in more detail below.

Ank Repeats (ANK). Some SEQ ID NOs represent polynucleotides encoding anAnk repeat-containing protein. The ankyrin motif is a 33 amino acidsequence named for the protein ankyrin which has 24 tandem 33-amino-acidmotifs. Ank repeats were originally identified in the cell-cycle-controlprotein cdc10 (Breeden et al., Nature (1987) 329:651). Proteinscontaining ankyrin repeats include ankyrin, myotropin, I-kappaBproteins, cell cycle protein cdc10, the Notch receptor (Matsuno et al.,Development (1997) 124(21):4265); G9a (or BAT8) of the class III regionof the major histocompatibility complex (Biochem J. 290:811-818, 1993),FABP, GABP, 53BP2, Lin12, glp-1, SW14, and SW16. The functions of theankyrin repeats are compatible with a role in protein-proteininteractions (Bork, Proteins (1993) 17(4):363; Lambert and Bennet, Eur.J. Biochem. (1993) 211:1; Kerr et al., Current Op. Cell Biol. (1992)4:496; Bennet et al., J. Biol. Chem. (1980) 255:6424).

ATPases Associated with Various Cellular Activities (ATPases). Some SEQID NOs correspond to a sequence that encodes a novel member of the“ATPases Associated with diverse cellular Activities” (AAA) proteinfamily. The AAA protein family is composed of a large number of ATPasesthat share a conserved region of about 220 amino acids that contains anATP-binding site (Froehlich et al., J. Cell Biol. (1991) 114:443;Erdmann et al., Cell (1991) 64:499; Peters et al., EMBO J. (1990)9:1757; Kunau et al., Biochimie (1993) 75:209-224; Confalonieri et al.,BioEssays (1995) 17:639;http://yeamob.pci.chemie.uni-tuebingen.de/AAA/Description.html). Theproteins that belong to this family either contain one or two AAAdomains. In general, the AAA domains in these proteins act asATP-dependent protein clamps (Confalonieri et al. (1995) BioEssays17:639). In addition to the ATP-binding ‘A’ and ‘B’ motifs, which arelocated in the N-terminal half of this domain, there is a highlyconserved region located in the central part of the domain which wasused in the development of the signature pattern.

Bromodomain (bromodomain). One SEQ ID NO represents a polynucleotideencoding a polypeptide having a bromodomain region (Haynes et al., 1992,Nucleic Acids Res. 20:2693-2603, Tamkun et al., 1992, Cell 68:561-572,and Tamkun, 1995, Curr. Opin. Genet. Dev. 5:473-477), which is aconserved region of about 70 amino acids. The bromodomain is thought tobe involved in protein-protein interactions and may be important for theassembly or activity of multicomponent complexes involved intranscriptional activation.

Basic Region Plus Leucine Zipper Transcription Factors (BZIP). Some SEQID NOs represent polynucleotides encoding a novel member of the familyof basic region plus leucine zipper transcription factors. The bZIPsuperfamily (Hurst, Protein Prof. (1995) 2:105; and Ellenberger, Curr.Opin. Struct. Biol. (1994) 4:12) of eukaryotic DNA-binding transcriptionfactors encompasses proteins that contain a basic region mediatingsequence-specific DNA-binding followed by a leucine zipper required fordimerization.

EF Hand (EFhand). Some SEQ ID NOs correspond to polynucleotides encodinga novel protein in the family of EF-hand proteins. Many calcium-bindingproteins belong to the same evolutionary family and share a type ofcalcium-binding domain known as the EF-hand (Kawasaki et al., Protein.Prof. (1995) 2:305-490). This type of domain consists of a twelveresidue loop flanked on both sides by a twelve residue alpha-helicaldomain. In an EF-hand loop the calcium ion is coordinated in apentagonal bipyramidal configuration. The six residues involved in thebinding are in positions 1, 3, 5, 7, 9 and 12; these residues aredenoted by X, Y, Z, −Y, −X and −Z. The invariant Glu or Asp at position12 provides two oxygens for liganding Ca (bidentate ligand).

Ets Domain (Ets_Nterm). One SEQ ID NO represents a polynucleotideencoding a polypeptide with N-terminal homology in ETS domain. Proteinsof this family contain a conserved domain, the “ETS-domain,” that isinvolved in DNA binding. The domain appears to recognize purine-richsequences; it is about 85 to 90 amino acids in length, and is rich inaromatic and positively charged residues (Wasylyk, et al., Eur. J.Biochem. (1993) 211:718). The ets gene family encodes a novel class ofDNA-binding proteins, each of which binds a specific DNA sequence andcomprises an ets domain that specifically interacts with sequencescontaining the common core tri-nucleotide sequence GGA. In addition toan ets domain, native ets proteins comprise other sequences which canmodulate the biological specificity of the protein. Ets genes andproteins are involved in a variety of essential biological processesincluding cell growth, differentiation and development, and threemembers are implicated in oncogenic process.

G-Protein Alpha Subunit (G-alpha). One SEQ ID NO represents apolynucleotide encoding a novel polypeptide of the G-protein alphasubunit family. Guanine nucleotide binding proteins (G-proteins) are afamily of membrane-associated proteins that coupleextracellularly-activated integral-membrane receptors to intracellulareffectors, such as ion channels and enzymes that vary the concentrationof second messenger molecules. G-proteins are composed of 3 subunits(alpha, beta and gamma) which, in the resting state, associate as atrimer at the inner face of the plasma membrane. The alpha subunit bindsGTP and exhibits GTPase activity. G-protein alpha subunits are 350-400amino acids in length and have molecular weights in the range 40-45 kDa.Seventeen distinct types of alpha subunit have been identified inmammals, and fall into 4 main groups on the basis of both sequencesimilarity and function: alpha-s, alpha-q, alpha-i and alpha-12 (Simonet al., Science (1993) 252:802). They are often N-terminally acylated,usually with myristate and/or palmitoylate, and these fatty acidmodifications can be important for membrane association andhigh-affinity interactions with other proteins.

Helicases conserved C-terminal domain (helicase_C). Some SEQ ID NOsrepresent polynucleotides encoding novel members of the DEAD/H helicasefamily. A number of eukaryotic and prokaryotic proteins have beencharacterized (Schmid S. R., et al., Mol. Microbiol. (1992) 6:283;Linder P., et al., Nature (1989) 337:121; Wassarman D. A., et al.,Nature (1991) 349:463) on the basis of their structural similarity. Allare involved in ATP-dependent, nucleic-acid unwinding. All DEAD boxfamily members of the above proteins share a number of conservedsequence motifs, some of which are specific to the DEAD family whileothers are shared by other ATP-binding proteins or by proteins belongingto the helicases ‘superfamily’ (Hodgman T. C., Nature (1988) 333:22 andNature (1988) 333:578 (Errata). One of these motifs, called the“D-E-A-D-box”, represents a special version of the B motif ofATP-binding proteins. Some other proteins belong to a subfamily whichhave His instead of the second Asp and are thus said to be “D-E-A-H-box”proteins (Wassarman D. A., et al., Nature (1991) 349:463; Harosh I., etal., Nucleic Acids Res. (1991) 19:6331; Koonin E. V. et al., J. Gen.Virol. (1992) 73:989.

Homeobox domain (homeobox). Some SEQ ID NOs represent polynucleotidesencoding proteins having a homeobox domain. The homeobox is a proteindomain of 60 amino acids (Gehring In: Guidebook to the Homeobox Genes,Duboule D., Ed., pp. 1-10, Oxford University Press, Oxford, (1994);Buerglin In: Guidebook to the Homeobox Genes, pp25-72, Oxford UniversityPress, Oxford, (1994); Gehring, Trends Biochem. Sci. (1992) 17:277-280;Gehring et al., Annu. Rev. Genet. (1986) 20:147-173; Schofield, TrendsNeurosci. (1987) 10:3-6) first identified in a number of Drosophilahomeotic and segmentation proteins. It is extremely well conserved inmany other animals, including vertebrates. This domain binds DNA througha helix-turn-helix type of structure. Several proteins that contain ahomeobox domain play an important role in development. Most of theseproteins are sequence-specific DNA-binding transcription factors. Thehomeobox domain is also very similar to a region of the yeast matingtype proteins. These are sequence-specific DNA-binding proteins that actas master switches in yeast differentiation by controlling geneexpression in a cell type-specific fashion.

A schematic representation of the homeobox domain is shown below. Thehelix-turn-helix region is shown by the symbols ‘H’ (for helix), and ‘t’(for turn).

The pattern detects homeobox sequences 24 residues long and spanspositions 34 to 57 of the homeobox domain.

MAP kinase kinase (mkk). Some SEQ ID NOs represent novel members of theMAP kinase kinase family. MAP kinases (MAPK) are involved in signaltransduction, and are important in cell cycle and cell growth controls.The MAP kinase kinases (MAPKK) are dual-specificity protein kinaseswhich phosphorylate and activate MAP kinases. MAPKK homologues have beenfound in yeast, invertebrates, amphibians, and mammals. Moreover, theMAPKK/MAPK phosphorylation switch constitutes a basic module activatedin distinct pathways in yeast and in vertebrates. MAPKKs are essentialtransducers through which signals must pass before reaching the nucleus.For review, see, e.g., Biologique Biol Cell (1993) 79:193-207; Nishidaet al., Trends Biochem Sci (1993) 18:128-31; Ruderman, Curr Opin CellBiol (1993) 5:207-13; Dhanasekaran et al., Oncogene (1998) 17:1447-55;Kiefer et al., Biochem Soc Trans (1997) 25:491-8; and Hill, Cell Signal(1996) 8:533-44.

Protein Kinase (protkinase). Some SEQ ID NOs represent polynucleotidesencoding protein kinases. Protein kinases catalyze phosphorylation ofproteins in a variety of pathways, and are implicated in cancer.Eukaryotic protein kinases (Hanks S. K., et al., FASEB J. (1995) 9:576;Hunter T., Meth. Enzymol. (1991) 200:3; Hanks S. K., et al., Meth.Enzymol. (1991) 200:38; Hanks S. K., Curr. Opin. Struct. Biol. (1991)1:369; Hanks S. K. et al., Science (1988) 241:42) are enzymes thatbelong to a very extensive family of proteins which share a conservedcatalytic core common to both serine/threonine and tyrosine proteinkinases. There are a number of conserved regions in the catalytic domainof protein kinases. The first region, which is located in the N-terminalextremity of the catalytic domain, is a glycine-rich stretch of residuesin the vicinity of a lysine residue, which has been shown to be involvedin ATP binding. The second region, which is located in the central partof the catalytic domain, contains a conserved aspartic acid residuewhich is important for the catalytic activity of the enzyme (Knighton D.R. et al., Science (1991) 253:407). The protein kinase profile includestwo signature patterns for this second region: one specific forserine/threonine kinases and the other for tyrosine kinases. A thirdprofile is based on the alignment in (Hanks S. K. et al., FASEB J.(1995) 9:576) and covers the entire catalytic domain.

If a protein analyzed includes two of the above protein kinasesignatures, the probability of it being a protein kinase is close to100%.

Ras family proteins (ras). Some SEQ ID NOs represent polynucleotidesencoding novel members of the ras family of small GTP/GDP-bindingproteins (Valencia et al., 1991, Biochemistry 30:4637-4648). Ras familymembers generally require a specific guanine nucleotide exchange factor(GEF) and a specific GTPase activating protein (GAP) as stimulators ofoverall GTPase activity. Among ras-related proteins, the highest degreeof sequence conservation is found in four regions that are directlyinvolved in guanine nucleotide binding. The first two constitute most ofthe phosphate and Mg2+ binding site (PM site) and are located in thefirst half of the G-domain. The other two regions are involved inguanosine binding and are located in the C-terminal half of themolecule. Motifs and conserved structural features of the ras-relatedproteins are described in Valencia et al., 1991, Biochemistry30:4637-4648.

Thioredoxin family active site (Thioredox). One SEQ ID NO represents apolynucleotide encoding a protein having a thioredoxin family activesite. Thioredoxins (Holmgren A., Annu. Rev. Biochem. (1985) 54:237;Gleason F. K. et al., FEMS Microbiol. Rev. (1988) 54:271; Holmgren, A.J. Biol. Chem. (1989) 264:13963; Eklund H. et al., Proteins (1991)11:13) are small proteins of approximately one hundred amino-acidresidues which participate in various redox reactions via the reversibleoxidation of an active center disulfide bond. They exist in either areduced form or an oxidized form where the two cysteine residues arelinked in an intramolecular disulfide bond. Thioredoxin is present inprokaryotes and eukaryotes and the sequence around the redox-activedisulfide bond is well conserved.

Trypsin (trypsin). One SEQ ID NO corresponds to a novel serine proteaseof the trypsin family. The catalytic activity of the serine proteasesfrom the trypsin family is provided by a charge relay system involvingan aspartic acid residue hydrogen-bonded to a histidine, which itself ishydrogen-bonded to a serine. The sequences in the vicinity of the activesite serine and histidine residues are well conserved in this family ofproteases (Brenner S., Nature (1988) 334:528).

WD Domain G-Beta Repeats (WD_domain). Some SEQ ID NOs represent novelmembers of the WD domain/G-beta repeat family. Beta-transducin (G-beta)is one of the three subunits (alpha, beta, and gamma) of the guaninenucleotide-binding proteins (G proteins) which act as intermediaries inthe transduction of signals generated by transmembrane receptors(Gilman, Annu. Rev. Biochem. (1987) 56:615). The alpha subunit binds toand hydrolyzes GTP; the functions of the beta and gamma subunits areless clear but they seem to be required for the replacement of GDP byGTP as well as for membrane anchoring and receptor recognition. Inhigher eukaryotes, G-beta exists as a small multigene family of highlyconserved proteins of about 340 amino acid residues. Structurally,G-beta consists of eight tandem repeats of about 40 residues, eachcontaining a central Trp-Asp motif (this type of repeat is sometimescalled a WD-40 repeat).

wnt Family of Developmental Signaling Proteins (Wnt_dev_sign). One SEQID NO corresponds to a novel member of the wnt family of developmentalsignaling proteins. Wnt-1 (previously known as int-1), the seminalmember of this family, (Nusse R., Trends Genet. (1988) 4:291) is thoughtto play a role in intercellular communication and seems to be asignalling molecule important in the development of the central nervoussystem (CNS). All wnt family proteins share the following featurescharacteristics of secretory proteins: a signal peptide, severalpotential N-glycosylation sites and 22 conserved cysteines that areprobably involved in disulfide bonds. The Wnt proteins seem to adhere tothe plasma membrane of the secreting cells and are therefore likely tosignal over only few cell diameters.

Protein Tyrosine Phosphatase (Y_phosphatase). One SEQ ID NO represents apolynucleotide encoding a protein tyrosine kinase. Tyrosine specificprotein phosphatases (EC 3.1.3.48) (PTPase) (Fischer et al., Science(1991) 253:401; Charbonneau et al., Annu. Rev. Cell Biol. (1992) 8:463;Trowbridge, J. Biol. Chem. (1991) 266:23517; Tonks et al., TrendsBiochem. Sci. (1989) 14:497; and Hunter, Cell (1989) 58:1013) catalyzethe removal of a phosphate group attached to a tyrosine residue. Theseenzymes are very important in the control of cell growth, proliferation,differentiation and transformation. Multiple forms of PTPase have beencharacterized and can be classified into two categories: soluble PTPasesand transmembrane receptor proteins that contain PTPase domain(s).Structurally, all known receptor PTPases are made up of a variablelength extracellular domain, followed by a transmembrane region and aC-terminal catalytic cytoplasmic domain. PTPase domains consist of about300 amino acids. The search of two conserved cysteines has been shown tobe absolutely required for activity. Furthermore, a number of conservedresidues in its immediate vicinity have also been shown to be important.

Zinc Finger C2H2 Type (Zincfing_C2H2). Some SEQ ID NOs correspond topolynucleotides encoding novel members of the of the C2H2 type zincfinger protein family. Zinc finger domains (Klug et al., Trends Biochem.Sci. (1987) 12:464; Evans et al., Cell (1988) 52:1; Payre et al., FEBSLett. (1988) 234:245; Miller et al., EMBO J. (1985) 4:1609; and Berg,Proc. Natl. Acad. Sci. USA (1988) 85:99) are nucleic acid-bindingprotein structures. In addition to the conserved zinc ligand residues,it has been shown that a number of other positions are also importantfor the structural integrity of the C2H2 zinc fingers. (Rosenfeld etal., J. Biomol. Struct. Dyn. (1993) 11:557) The best conserved positionis found four residues after the second cysteine; it is generally anaromatic or aliphatic residue.

Src homology 2. Some SEQ ID NOs represent polynucleotides encoding novelmembers of the family of Src homology 2 (SH2) proteins. The Src homology2 (SH2) domain is a protein domain of about 100 amino acid residuesfirst identified as a conserved sequence region between the oncoproteinsSrc and Fps (Sadowski I. et al., Mol. Cell. Biol. 6:4396-4408 (1986)).Similar sequences are found in many other intracellularsignal-transducing proteins (Russel R. B. et al., FEBS Lett. 304:15-20(1992)). SH2 domains function as regulatory modules of intracellularsignalling cascades by interacting with high affinity tophosphotyrosine-containing target peptides in a sequence-specific andphosphorylation-dependent manner (Marangere L. E. M., Pawson T., J. CellSci. Suppl. 18:97-104 (1994); Pawson T., Schlessinger J., Curr. Biol.3:434-442 (1993); Mayer B. J., Baltimore D., Trends Cell. Biol. 3:8-13(1993); Pawson T., Nature 373:573-580 (1995)).

The SH2 domain has a conserved 3D structure consisting of two alphahelices and six to seven beta-strands. The core of the domain is formedby a continuous beta-meander composed of two connected beta-sheets(Kuriyan J., Cowburn D., Curr. Opin. Struct. Biol. 3:828-837(1993)). Theprofile to detect SH2 domains is based on a structural alignmentconsisting of 8 gap-free blocks and 7 linker regions totaling 92 matchpositions.

Src homology 3. Some SEQ ID NOs represent polynucleotides encoding novelmembers of the family of Src homology 3 (SH3) proteins. The Src homology3 (SH3) domain is a small protein domain of about 60 amino acid residuesfirst identified as a conserved sequence in the non-catalytic part ofseveral cytoplasmic protein tyrosine kinases (e.g., Src, Abl, Lck)(Mayer B. J. et al., Nature 332:272-275 (1988)). Since then, it has beenfound in a great variety of other intracellular or membrane-associatedproteins (Musacchio A. et al., FEBS Lett. 307:55-61 (1992); Pawson T.,Schlessinger J., Curr. Biol. 3:434-442 (1993); Mayer B. J., BaltimoreD., Trends Cell Biol. 3:8-13 (1993); Pawson T., Nature 373:573-580(1995)).

The SH3 domain has a characteristic fold which consists of five or sixbeta strands arranged as two tightly packed anti-parallel beta sheets.The linker regions may contain short helices (Kuriyan J., Cowburn D.,Curr. Opin. Struct. Biol. 3:828-837 (1993)).

The function of the SH3 domain may be to mediate assembly of specificprotein complexes via binding to proline-rich peptides (Morton C. J.,Campbell I. D., Curr. Biol. 4:615-617 (1994)).

In general SH3 domains are found as single copies in a given protein,but there are a significant number of proteins with two SH3 domains anda few with 3 or 4 copies.

Fibronectin type III. Some SEQ ID NOs represent polynucleotides encodingnovel members of the family of fibronectin type III proteins. A numberof receptors for lymphokines, hematopoeitic growth factors and growthhormone-related molecules have been found to share a common bindingdomain. (Bazan J. F., Biochem. Biophys. Res. Commun. 164:788-795 (1989);Bazan J. F., Proc. Natl. Acad. Sci. U.S.A. 87:6934-6938 (1990); CosmanD. et al., Trends Biochem. Sci. 15:265-270 (1990); d'Andrea A. D.,Fasman G. D., Lodish H. F., Cell 58:1023-1024 (1989); d'Andrea A. D.,Fasman G. D., Lodish H. F., Curr. Opin. Cell Biol. 2:648-651 (1990)).

The conserved region constitutes all or part of the extracellularligand-binding region and is about 200 amino acid residues long. In theN-terminal of this domain there are two pairs of cysteines known, in thegrowth hormone receptor, to be involved in disulfide bonds.

Two patterns detect this family of receptors. The first one is derivedfrom the first N-terminal disulfide loop, the second is atryptophan-rich pattern located at the C-terminal extremity of theextracellular region.

LIM domain containing proteins. Some SEQ ID NOs representpolynucleotides encoding novel members of the family of LIM domaincontaining proteins. A number of proteins contain a conservedcysteine-rich domain of about 60 amino-acid residues. (Freyd G. et al.,Nature 344:876-879 (1990); Baltz R. et al., Plant Cell 4:1465-1466(1992); Sanchez-Garcia I., Rabbitts T. H., Trends Genet. 10:315-320(1994)).

In the LIM domain, there are seven conserved cysteine residues and ahistidine.

C2 domain (protein kinase C like). Some SEQ ID NOs representpolynucleotides encoding novel members of the family of C2 domaincontaining proteins. Some isozymes of protein kinase C (PKC) contain adomain, known as C2, of about 116 amino-acid residues, which is locatedbetween the two copies of the C1 domain (that bind phorbol esters anddiacylglycerol) and the protein kinase catalytic domain. (Azzi A. etal., Eur. J. Biochem. 208:547-557 (1992); Stabel S., Semin. Cancer Biol.5:277-284 (1994)).

The C2 domain is involved in calcium-dependent phospholipid binding(Davletov B. A., Suedhof T. C., J. Biol. Chem. 268:26386-26390 (1993)).Since domains related to the C2 domain are also found in proteins thatdo not bind calcium, other putative functions for the C2 domain includebinding to inositol-1,3,5-tetraphosphate. (Fukuda M., et al., J. Biol.Chem. 269:29206-29211 (1994).)

The consensus pattern for the C2 domain is located in a conserved partof that domain, the connecting loop between beta strands 2 and 3. Theprofile for the C2 domain covers the total domain.

Serine proteases, trypsin family, active sites. One SEQ ID NO representsa polynucleotide encoding a novel member of the family of serineprotease, trypsin proteins. The catalytic activity of the serineproteases from the trypsin family is provided by a charge relay systeminvolving an aspartic acid residue hydrogen-bonded to a histidine, whichitself is hydrogen-bonded to a serine. The sequences in the vicinity ofthe active site serine and histidine residues are well conserved in thisfamily of proteases (Brenner S., Nature 334:528-530 (1988)).

RNA Recognition Motif Domain (RRM, RBD, or RNP). Some SEQ ID NOsrepresent polynucleotides encoding novel members of the family of RNArecognition motif domain proteins (Bandziulis R. J. et al., Genes Dev.3:431-437 (1989); Dreyfuss G. et al., Trends Biochem. Sci. 13:86-91(1988)).

Inside the putative RNA-binding domain there are two regions which arehighly conserved. The first one is a hydrophobic segment of six residues(which is called the RNP-2 motif); the second one is an octapeptidemotif (which is called RNP-1 or RNP-CS). The position of both motifs inthe domain is shown in the following schematic representation:

Phosphatidylinositol-specific phospholipase C, Y Domain. One SEQ ID NOrepresents a polynucleotide encoding a novel member of thephosphatidylinositol-specific phospholipase C, Y domain family ofproteins. Phosphatidylinositol-specific phospholipase C (EC3.1.4.11), aeukaryotic intracellular enzyme, plays an important role in signaltransduction processes (Meldrum E. et al., Biochim. Biophys. Acta1092:49-71 (1991)). It catalyzes the hydrolysis of1-phosphatidyl-D-myo-inositol-3,4,5-triphosphate into the secondmessenger molecules diacylglycerol and inositol-1,4,5-triphosphate. Thiscatalytic process is tightly regulated by reversible phosphorylation andbinding of regulatory proteins (Rhee S. G., Choi K. D., Adv. SecondMessenger Phosphoprotein Res. 26:35-61 (1992); Rhee S. G., Choi K. D.,J. Biol. Chem. 267:12393-12396 (1992); Sternweis P. C., Smrcka A. V.,Trends Biochem. Sci. 17:502-506 (1992)).

All eukaryotic PI-PLCs contain two regions of homology, referred to as“X-box” and “Y-box”. The order of these two regions is the same(NH2-X—Y—COOH), but the spacing is variable. In most isoforms, thedistance between these two regions is only 50-100 residues but in thegamma isoforms one PH domain, two SH2 domains, and one SH3 domain areinserted between the two PLC-specific domains. The two conserved regionshave been shown to be important for the catalytic activity. At theC-terminal of the Y-box, there is a C2 domain possibly involved inCa-dependent membrane attachment.

Serine Carboxypeptidases. One SEQ ID NO represents a polynucleotideencoding a novel member of the serine carboxypeptidases family ofproteins. Carboxypeptidases may be either metallo carboxypeptidases orserine carboxypeptidases (EC 3.4.16.5 and EC 3.4.16.6). The catalyticactivity of the serine carboxypeptidases, like that of the trypsinfamily serine proteases, is provided by a charge relay system involvingan aspartic acid residue hydrogen-bonded to a histidine, which is itselfhydrogen-bonded to a serine (Liao D. I., Remington S. J., J. Biol. Chem.265:6528-6531 (1990)).

dsrm Double-Stranded RNA Binding Motif. One SEQ ID NO represents apolynucleotide encoding a novel member of the dsrm double-stranded RNAbinding motif proteins. In eukaryotic cells, a multitude of RNA-bindingproteins play key roles in the posttranscriptional regulation of geneexpression. Characterization of these proteins has led to theidentification of several RNA-binding motifs. Several human and othervertebrate genetic disorders are caused by aberrant expression ofRNA-binding proteins. (C. G. Burd & G. Dreyfuss, Science 265: 615-621(1994)).

Proteins containing double stranded RNA binding motifs bind to specificRNA targets. Double stranded RNA binding motifs are exemplified byinterferon-induced protein kinase in humans, which is part of thecellular response to dsRNA.

Some SEQ ID NOs encode members of the 4 trans-membrane integral membraneprotein family. This family consists of type III proteins, which areintegral membrane proteins that contain a N-terminal membrane-anchoringdomain that is not cleaved during biosynthesis, and which functions as atranslocation signal and a membrane anchor. The proteins also have threeadditional transmembrane regions.

One SEQ ID NO encodes a polypeptide having a calpain large subunit,domain III. Calpains are a family of intracellular proteases that play avariety of biological roles. Calpain 3, also known as p94, ispredominantly expressed in skeletal muscle and plays a role inlimb-girdle muscular dystrophy type 2A. (Sorimachi, H. et al., Biochem.J. 328:721-732, 1997).

Some SEQ ID NOs encode polypeptides having a C3HC4 type zinc fingerdomain (RING finger), which is a cysteine-rich domain of 40 to 60residues that binds two atoms of zinc, and is believed to be involved inmediating protein-protein interactions. Mammalian proteins of thisfamily include V(D)J recombination activating protein, which activatesthe rearrangement of immunoglobulin and T-cell receptor genes; breastcancer type 1 susceptibility protein (BRCA1); bmi-1 proto-oncogene; cblproto-oncogene; and mel-18 protein, which is expressed in a variety oftumor cells and is a transcriptional repressor that recognizes and bindsa specific DNA sequence.

One SEQ ID NO encodes a eukaryotic transcription factor with a fork headdomain, of about 100 amino acid residues. Proteins of this group aretranscription factors, including mammalian transcription factorsHNF-3-alpha, -beta, and -gamma; interleukin-enhancer binding factor; andHTLF, which binds to a region of human T-cell leukemia virus longterminal repeat.

One SEQ ID NO encodes a polypeptide having a PDZ domain. Several dozensignaling proteins belong to this group of proteins that have 80-100residue repeats known as PDZ domains. Several of the proteins interactwith the C-terminal tetrapeptide motifs X-Ser/Thr/X-Val-COO— of ionchannels and/or receptors. (Ponting, C. P., Protein Sci. 6;464-468,1997.)

One SEQ ID NO encodes a polypeptide in the family of phorbolesters/glycerol binding proteins. Phorbol esters (PE) are analogues ofdiacylglycerol (DAG) and potent tumor promoters. DAG activates a familyof serine-threonine protein kinases, known as protein kinase C. TheN-terminal region of protein kinase C binds PE and DAG, and contains oneor two copies of a cysteine-rich domain of about 50 amino acid residues.Other proteins having this domain include diacylglycerol kinase; the vavoncogene; and N-chimaerin, a brain-specific protein. The DAG/PE bindingdomain binds two zinc ions through the six cysteines and two histidinesthat are conserved in the domain.

One SEQ ID NO encodes a polypeptide having a WW/rsp5/WWP domain. Theprotein is named for the presence of conserved aromatic positions,generally tryptophan, as well as a conserved proline. Proteins havingthe domain include dystrophin, vertebrate YAP protein, and IQGAP, ahuman GTPase activating protein which acts on ras.

One SEQ ID NO encodes a member of the dual specificity phosphatasefamily, having a catalytic domain, and some SEQ IDS NOs encode membersof the protein tyrosine phosphatase family. These families are relatedand classified as tyrosine specific protein phosphatases. The enzymescatalyze the removal of a phosphate group from a tyrosine residue, andare important in the control of cell growth, proliferation,differentiation, and transformation. TABLE 87 SEQ ID Start Stop ScoreDirection Description 9948 295 421 5872 For mkk like kinases 9949 31 1823943 For Basic region plus leucine zipper transcription factors 9950 298397 5625 For mkk like kinases 10105 175 395 7660 For SH2 Domain 10106358 432 4320 For Ank repeat 10115 37 322 6049 For mkk like kinases 1015323 121 4607 For SH3 Domain 10227 110 172 4150 For Zinc finger, C2H2 type10329 42 191 4036 For Basic region plus leucine zipper transcriptionfactors 10350 71 428 5538 Rev ATPases Associated with Various CellularActivities 10471 116 288 3930 Rev Basic region plus leucine zippertranscription factors 10558 157 561 5797 For ATPases Associated withVarious Cellular Activities 10665 209 427 5379 For Fibronectin type IIIdomain 10687 116 288 3930 For Basic region plus leucine zippertranscription factors 10726 339 392 3620 For Zinc finger, C2H2 type10739 341 406 2930 Rev EF-hand 10741 108 262 4179 For Basic region plusleucine zipper transcription factors 10755 158 353 4430 For Basic regionplus leucine zipper transcription factors 11076 41 444 5279 Rev proteinkinase 11111 186 416 5469 For Fibronectin type III domain 11187 238 3153540 For Ank repeat 11188 79 240 11640 For LIM domain containingproteins 11207 73 234 3953 For Basic region plus leucine zippertranscription factors 11228 248 404 8226 for LIM domain containingproteins 11243 294 356 4690 for Zinc finger, C2H2 type 11244 1 234 8981for C2 domain (prot. kinase C like) 11255 66 164 6390 for WD domain,G-beta repeats 11279 222 377 8686 for LIM domain containing proteins11284 69 257 5221 for Basic region plus leucine zipper transcriptionfactors 11299 42 140 7130 for WD domain, G-beta repeats 11305 243 3988736 for LIM domain containing proteins 11329 222 350 10553 for Trypsin11336 8 354 6073 for Protein Tyrosine Phosphatase 11373 49 209 3996 forBasic region plus leucine zipper transcription factors 11383 4 180 4978for RNA recognition motif. (aka RRM, RBD, or RNP domain) 11397 54 4375176 for protein kinase 11415 241 520 3929 for Helicases conservedC-terminal domain 11415 40 612 5187 for protein kinase 11422 154 2164870 for Zinc finger, C2H2 type 11433 2 252 4662 for RNA recognitionmotif. (aka RRM, RBD, or RNP domain) 11446 156 212 3520 for Zinc finger,C2H2 type 11457 9 635 11087 for wnt family of developmental signalingproteins 11459 289 471 4107 for Basic region plus leucine zippertranscription factors 11468 200 391 4118 for Basic region plus leucinezipper transcription factors 11475 163 354 3958 for Basic region plusleucine zipper transcription factors 11476 207 398 4038 for Basic regionplus leucine zipper transcription factors 11482 107 298 3978 for Basicregion plus leucine zipper transcription factors 11541 180 365 4022 forBasic region plus leucine zipper transcription factors 11549 100 2913998 for Basic region plus leucine zipper transcription factors 11593196 258 4880 for Zinc finger, C2H2 type 11595 9 86 6610 for HomeoboxDomain 11596 316 369 5780 rev Thioredoxins 11607 109 410 17414 for Rasfamily 11623 184 372 3977 for Basic region plus leucine zippertranscription factors 11626 92 439 24100 revPhosphatidylinositol-specific phospholipase C, Y domain 11630 263 3616400 for WD domain, G-beta repeats 11663 238 433 10572 rev Serinecarboxypeptidases 11674 281 367 2580 for EF-hand 11681 236 334 5880 forWD domain, G-beta repeats 11698 64 126 4790 for Zinc finger, C2H2 type.11720 295 351 4030 for Zinc finger, C2H2 type 11723 301 378 3460 for Ankrepeat 11727 36 161 4170 for Basic region plus leucine zippertranscription factors 11730 184 315 8390 for N-terminal homology in Etsdomain 11733 127 294 10770 for Bromodomain (conserved sequence found inhuman, Drosophila and yeast proteins.) 11737 9 146 4741 forDouble-stranded RNA binding motif 11738 278 355 3460 for Ank repeat11739 123 299 12150 for Homeobox Domain 11740 127 303 12180 for HomeoboxDomain 11749 184 267 4270 for Ank repeat 11751 18 173 8987 for SH3Domain 11754 51 206 8987 for SH3 Domain 11758 224 307 4270 for Ankrepeat 11765 12 398 36700 for G-protein alpha subunit 11828 160 258 6370for WD domain, G-beta repeats 11830 35 151 9335 for Zinc finger, C3HC4type (RING finger) 11899 60 197 7917 for Zinc finger, C3HC4 type (RINGfinger) 11984 253 306 5410 for Zinc finger, CCHC class 12054 2 401 10596for ATPases Associated with Various Cellular Activities 12135 90 1795380 for WW/rsp5/WWP domain containing proteins 12137 127 225 5500 forWD domain, G-beta repeats 12200 20 387 6044 for Protein TyrosinePhosphatase 12201 183 353 5136 for C2 domain (prot. kinase C like) 1220512 382 5228 for protein kinase 12229 20 371 5962 for Protein TyrosinePhosphatase 12282 48 211 4132 for Basic region plus leucine zippertranscription factors 12343 43 194 3996 for Basic region plus leucinezipper transcription factors 12347 25 350 4675 for Dual specificityphosphatase, catalytic domain 12481 18 101 4560 for Ank repeat 12496 0311 10295 for 4 transmembrane segments integral membrane proteins 1251060 165 4560 for SH2 Domain 12603 9 461 5759 for ATPases Associated withVarious Cellular Activities 12745 116 400 16107 for DEAD and DEAH boxhelicases 12778 100 320 5550 rev ATPases Associated with VariousCellular Activities 12790 198 392 9384 for DEAD and DEAH box helicases12863 18 281 10480 for Calpain large subunit, domain III 12888 5 3875976 rev protein kinase 12934 131 214 3600 for Ank repeat 12966 191 2925295 for WD domain, G-beta repeats 13000 190 252 4360 for Zinc finger,C2H2 type 13027 275 367 5791 for WD domain, G-beta repeats 13066 190 3694022 for Basic region plus leucine zipper transcription factors 13071129 320 3947 for Basic region plus leucine zipper transcription factors13077 167 334 4180 for Basic region plus leucine zipper transcriptionfactors 13094 14 164 5951 for mkk like kinases 13094 8 112 5968 forprotein kinase 13097 45 386 19398 for ATPases Associated with VariousCellular Activities 13102 14 215 9133 for 4 transmembrane segmentsintegral membrane proteins 13109 229 390 6089 for mkk like kinases 13109118 390 8063 for protein kinase 13112 293 355 3570 for Zinc finger, C2H2type 13114 0 215 10146 for 4 transmembrane segments integral membraneproteins 13116 281 343 4490 for Zinc finger, C2H2 type 13127 34 256 4190for Basic region plus leucine zipper transcription factors 13177 138 3949877 for Ras family 13185 8 139 9328 for ATPases Associated with VariousCellular Activities 13186 97 180 3820 for Ank repeat 13193 11 187 15442for Fork head domain, eukaryotic transcription factors 13200 15 182 9681for mkk like kinases 13204 16 102 4680 for EF-hand 13211 208 300 5585for WD domain, G-beta repeats. 13216 7 153 6100 for Helicases conservedC-terminal domain 13225 161 223 4900 for Zinc finger, C2H2 type 13226 43321 8740 for SH2 Domain 1 3258 94 342 14970 for SH2 Domain 13264 65 27112512 for PDZ domain 13270 124 270 6068 for Phorbolesters/diacylglycerol binding

Example 58 Differential Expression of Polynucleotides of the Invention:Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the inventionwas assessed in several libraries prepared from various sources,including cell lines and patient tissue samples. Table 88 provides asummary of these libraries, including the shortened library name (usedhereafter), the mRNA source used to prepare the cDNA library, theabbreviated name of the library that is used in the tables below (inquotes), and the approximate number of clones in the library. TABLE 88Description of cDNA Libraries Number of Clones in Library this (lib #)Description Clustering 1 Km12 L4 307133 Human Colon Cell Line, HighMetastatic Potential (derived from Km12C) “High Colon” 2 Km12C 284755Human Colon Cell Line, Low Metastatic Potential “Low Colon” 3 MDA-MB-231326937 Human Breast Cancer Cell Line, High Metastatic Potential;micro-metastases in lung “High Breast” 4 MCF7 318979 Human Breast CancerCell, Non Metastatic “Low Breast” 8 MV-522 223620 Human Lung Cancer CellLine, High Metastatic Potential “High Lung” 9 UCP-3 312503 Human LungCancer Cell Line, Low Metastatic Potential “Low Lung” 12 Humanmicrovascular endothelial cells (HMEC) - 41938 Untreated PCR (OligodT)cDNA library 13 Human microvascular endothelial cells (HMEC) - 42100Basic fibroblast growth factor (bFGF) treated PCR (OligodT) cDNA library14 Human microvascular endothelial cells (HMEC) - 42825 Vascularendothelial growth factor (VEGF) treated PCR (OligodT) cDNA library 15Normal Colon - UC#2 Patient 34285 PCR (OligodT) cDNA library “NormalColon Tumor Tissue” 16 Colon Tumor - UC#2 Patient 35625 PCR (OligodT)cDNA library “Normal Colon Tumor Tissue” 17 Liver Metastasis from ColonTumor of UC#2 36984 Patient PCR (OligodT) cDNA library “High ColonMetastasis Tissue” 18 Normal Colon - UC#3 Patient 36216 PCR (OligodT)cDNA library “Normal Colon Tumor Tissue” 19 Colon Tumor - UC#3 Patient41388 PCR (OligodT) cDNA library “High Colon Tumor Tissue” 20 LiverMetastasis from Colon Tumor of UC#3 30956 Patient PCR (OligodT) cDNAlibrary “High Colon Metastasis Tissue” 21 G RRpz 164801 Human ProstateCell Line 22 WOca 162088 Human Prostate Cancer Cell Line

The KM12L4 and KM12C cell lines are described in Example 55 above. TheMDA-MB-231 cell line was originally isolated from pleural effusions(Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastaticpotential, and forms poorly differentiated adenocarcinoma grade II innude mice consistent with breast carcinoma. The MCF7 cell line wasderived from a pleural effusion of a breast adenocarcinoma and isnon-metastatic. The MV-522 cell line is derived from a human lungcarcinoma and is of high metastatic potential. The UCP-3 cell line is alow metastatic human lung carcinoma cell line; the MV-522 is a highmetastatic variant of UCP-3. These cell lines are well-recognized in theart as models for the study of human breast and lung cancer (see, e.g.,Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7);Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ransonet al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al.,Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al.,Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990)11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637;(MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); andZhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples oflibraries 15-20 are derived from two different patients (UC#2, andUC#3). The bFGF-treated HMEC were prepared by incubation with bFGF at 10ng/ml for 2 hrs; the VEGF-treated HMEC were prepared by incubation with20 ng/ml VEGF for 2 hrs. Following incubation with the respective growthfactor, the cells were washed and lysis buffer added for RNApreparation. The GRRpz cell line refers to low passage (3 passages orfewer) human prostate cells, and the WOca cell line refers to lowpassage (3 passages or fewer) human prostate cancer cells.

Each of the libraries is composed of a collection of cDNA clones that inturn are representative of the mRNAs expressed in the indicated mRNAsource. In order to facilitate the analysis of the millions of sequencesin each library, the sequences were assigned to clusters. The concept of“cluster of clones” is derived from a sorting/grouping of cDNA clonesbased on their hybridization pattern to a panel of roughly 300 7 bpoligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29).Random cDNA clones from a tissue library are hybridized at moderatestringency to 300 7 bp oligonucleotides. Each oligonucleotide has somemeasure of specific hybridization to that specific clone. Thecombination of 300 of these measures of hybridization for 300 probesequals the “hybridization signature” for a specific clone. Clones withsimilar sequence will have similar hybridization signatures. Bydeveloping a sorting/grouping algorithm to analyze these signatures,groups of clones in a library can be identified and brought togethercomputationally. These groups of clones are termed “clusters”. Dependingon the stringency of the selection in the algorithm (similar to thestringency of hybridization in a classic library cDNA screeningprotocol), the “purity” of each cluster can be controlled. For example,artifacts of clustering may occur in computational clustering just asartifacts can occur in “wet-lab” screening of a cDNA library with 400 bpcDNA fragments, at even the highest stringency. The stringency used inthe implementation of cluster herein provides groups of clones that arein general from the same cDNA or closely related cDNAs. Closely relatedclones can be a result of different length clones of the same cDNA,closely related clones from highly related gene families, or splicevariants of the same cDNA.

Differential expression for a selected cluster was assessed by firstdetermining the number of cDNA clones corresponding to the selectedcluster in the first library (Clones in 1^(st)), and the determining thenumber of cDNA clones corresponding to the selected cluster in thesecond library (Clones in 2^(nd)). Differential expression of theselected cluster in the first library relative to the second library isexpressed as a “ratio” of percent expression between the two libraries.In general, the “ratio” is calculated by: 1) calculating the percentexpression of the selected cluster in the first library by dividing thenumber of clones corresponding to a selected cluster in the firstlibrary by the total number of clones analyzed from the first library;2) calculating the percent expression of the selected cluster in thesecond library by dividing the number of clones corresponding to aselected cluster in a second library by the total number of clonesanalyzed from the second library; 3) dividing the calculated percentexpression from the first library by the calculated percent expressionfrom the second library. If the “number of clones” corresponding to aselected cluster in a library is zero, the value is set at 1 to aid incalculation. The formula used in calculating the ratio takes intoaccount the “depth” of each of the libraries being compared, i.e., thetotal number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentiallyexpressed between two samples when the ratio value is greater than atleast about 2, preferably greater than at least about 3, more preferablygreater than at least about 5, where the ratio value is calculated usingthe method described above. The significance of differential expressionis determined using a z score test (Zar, Biostatistical Analysis,Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298(1974)).

Example 59 Polynucleotides Differentially Expressed in High MetastaticPotential Breast Cancer Cells Versus Low Metastatic Breast Cancer Cells

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential breast cancer tissue and low metastatic breast cancer cells.Expression of these sequences in breast cancer can be valuable indetermining diagnostic, prognostic and/or treatment information. Forexample, sequences that are highly expressed in the high metastaticpotential cells can be indicative of increased expression of genes orregulatory sequences involved in the metastatic process. A patientsample displaying an increased level of one or more of thesepolynucleotides may thus warrant more aggressive treatment. In anotherexample, sequences that display higher expression in the low metastaticpotential cells can be associated with genes or regulatory sequencesthat inhibit metastasis, and thus the expression of thesepolynucleotides in a sample may warrant a more positive prognosis thanthe gross pathology would suggest.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic maker, for risk assessment, patienttreatment and the like. These polynucleotide sequence can also be usedin combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentiallyexpressed between high metastatic potential breast cancer cells and lowmetastatic potential breast cancer cells. TABLE 89 Differentiallyexpressed polynucleotides: Higher expression in high metastaticpotential breast cancer (lib3) relative to low metastatic breast cancercells (lib4) SEQ ID NOs: Lib3 clones Lib4 clones lib3/lib4 472 64 0 6211770 6 0 6 11775 8 0 8 11786 6 0 6 11791 6 0 6 11794 12 3 4 11842 89 224 12037 7 0 7 12038 7 0 7 12054 37 13 3 12109 19 0 19 12112 16 5 3 1215112 2 6 12158 6 0 6 12257 21 2 10 12297 16 4 4 12313 6 0 6 12314 6 0 612409 13 3 4 12424 16 2 8 12459 8 1 8 12461 11 1 11 12526 11 2 5 1255922 5 4 12593 8 0 8 12598 19 0 19 12603 14 4 3 12626 8 0 8 12643 9 0 912676 6 0 6 12695 10 0 10 12723 13 2 6 12737 6 0 6 12825 14 0 14 1287826 8 3 12883 17 4 4 12887 6 0 6 12896 22 3 7 12899 13 1 13 12929 6 0 612962 10 1 10 12990 33 12 3 12991 9 1 9 13014 19 3 6 13016 11 2 5 1309212 2 6 13122 8 1 8 13129 27 8 3 13131 13 1 13 13203 8 0 8 13207 6 0 613250 14 3 5 13254 13 1 13

TABLE 90 Differentially expressed polynucleotides: Higher expression inlow metastatic breast cancer cells (lib4) relative to high metastaticpotential breast cancer (lib3) SEQ ID Lib 3 Lib 4 NOs: Clones Cloneslib4/lib3 10321 0 6 6 10533 3 21 7 10543 0 6 6 10545 0 8 8 10631 0 9 910663 0 7 7 11244 2 29 15 11371 2 13 7 11799 0 9 9 11834 0 7 7 11870 0 66 11874 8 32 4 11934 0 7 7 11965 0 7 7 11995 1 22 23 12006 0 6 6 12043 09 9 12064 0 8 8 12081 0 6 6 12082 0 12 12 12083 5 19 4 12091 2 15 812111 5 16 3 12163 20 43 2 12185 3 18 6 12232 24 56 2 12265 1 13 1312274 0 10 10 12290 0 6 6 12312 1 17 17 12323 1 21 22 12362 0 6 6 123790 11 11 12442 0 6 6 12494 1 10 10 12497 0 6 6 12503 1 17 17 12509 0 6 612528 1 9 9 12551 5 24 5 12633 5 24 5 12647 0 6 6 12671 1 14 14 12713 415 4 12745 0 7 7 12906 5 15 3 12924 1 14 14 12928 20 58 3 12966 4 17 412976 2 17 9 12994 2 11 6 12995 0 6 6 13021 0 6 6 13047 15 52 4 13051 1552 4 13061 0 6 6 13106 22 49 2 13172 23 96 4 13201 19 46 2 13204 20 40 213265 0 9 9

Example 60 Polynucleotides Differentially Expressed in High MetastaticPotential Lung Cancer Cells Versus Low Metastatic Lung Cancer Cells

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential lung cancer cells and low metastatic lung cancer cells.Expression of these sequences in lung cancer tissue can be valuable indetermining diagnostic, prognostic and/or treatment information. Forexample, sequences that are highly expressed in the high metastaticpotential cells can be indicative of increased expression of genes orregulatory sequences involved in the metastatic process. A patientsample displaying an increased level of one or more of thesepolynucleotides may thus warrant more aggressive treatment. In anotherexample, sequences that display higher expression in the low metastaticpotential cells can be associated with genes or regulatory sequencesthat inhibit metastasis, and thus the expression of thesepolynucleotides in a sample may warrant a more positive prognosis thanthe gross pathology would suggest.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic marker, for risk assessment, patienttreatment and the like. These polynucleotide sequences can also be usedin combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentiallyexpressed between high metastatic potential lung cancer cells and lowmetastatic potential lung cancer cells: TABLE 91 Differentiallyexpressed polynucleotides: Higher expression in high metastaticpotential lung cancer cells (lib8) relative to low metastatic lungcancer cells (lib9) SEQ ID NO: Lib8 clones Lib9 clones lib8/lib9 9933 100 10 10056 5 0 5 10070 5 0 7 10071 9 0 13 10090 6 0 8 10119 10 0 1410173 5 0 7 10181 5 0 7 10190 5 0 7 10267 6 1 8 10331 5 0 7 10426 5 0 710439 6 0 8 10449 5 0 7 10507 5 0 7 10542 7 0 10 10556 7 0 10 10579 5 07 10597 8 0 11 10599 5 0 7 10619 9 2 6 10633 28 13 3 10693 11 0 15 107315 0 7 10753 8 2 6 10820 11 2 8 11087 5 0 7 11252 6 0 8 11271 5 0 7 1144311 1 15 11625 5 0 7 11671 17 9 3 11687 20 4 7 11688 5 0 7 11699 6 0 811700 40 3 19 11718 6 1 8 11722 6 1 8 11730 16 9 2 11803 6 0 8 11838 8 111 11858 6 0 8 11894 43 9 7 11943 12 1 17 11964 8 1 11 11979 20 13 211990 16 4 6 12047 5 0 7 12096 10 2 7 12100 44 13 5 12103 11 1 15 1210410 4 3 12202 7 0 10 12230 10 4 3 12233 10 0 14 12312 14 6 3 12317 6 1 812379 10 4 3 12433 6 0 8 12516 5 0 7 12576 8 2 6 12588 6 1 8 12589 6 1 812966 21 3 10 12969 16 5 4 13011 7 1 10 13059 181 119 2 13076 5 0 713106 16 5 4 13129 5 0 7 13139 28 4 10 13155 7 1 10 13168 16 0 22 131838 2 6 13224 7 0 10 13228 20 0 28 13237 24 4 8 13249 5 0 7 13250 5 0 7

TABLE 92 Differentially expressed polynucleotides: Higher expression inlow metastatic lung cancer cells (lib 9) relative to high metastaticpotential lung cancer cells (lib 8) SEQ ID NO: Lib 8 clones Lib 9 cloneslib 9/lib 8 9943 3 20 5 9972 0 18 13 9983 0 8 6 9989 0 11 8 10024 10 665 10048 0 16 11 10133 1 14 10 10152 4 35 6 10156 0 13 9 10183 0 29 2110248 2 17 6 10287 1 37 26 10289 0 11 8 10337 0 8 6 10369 0 9 6 10380 09 6 10403 0 26 19 10413 0 41 29 10436 1 12 9 10441 1 11 8 10500 1 17 1210533 3 23 5 10625 0 11 8 10645 5 23 3 10725 0 14 10 10743 0 9 6 10755 114 10 10793 0 12 9 10819 5 21 3 10936 2 14 5 11063 0 8 6 11073 0 12 911085 2 45 16 11089 1 13 9 11221 2 13 5 11245 1 13 9 11246 1 13 9 112860 12 9 11296 0 12 9 11356 2 18 6 11361 1 14 10 11385 0 13 9 11395 0 13 911414 0 8 6 11415 1 13 9 11583 38 253 5 11601 1 17 12 11606 0 9 6 116770 8 6 11736 4 18 3 11756 3 16 4 11764 3 23 5 11775 2 17 6 11829 1 18 1312065 2 16 9 12075 0 9 6 12382 0 12 9 12643 10 38 3 12668 403 2000 412720 6 25 3 12912 3 18 4 12999 0 10 7 13026 3 23 5 13211 0 20 14 13243110 548 4

Example 61 Polynucleotides Differentially Expressed in High MetastaticPotential Colon Cancer Cells Versus Low Metastatic Colon Cancer Cells

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential colon cancer cells and low metastatic colon cancer cells.Expression of these sequences in colon cancer tissue can providediagnostic, prognostic and/or treatment information. For example,sequences that are highly expressed in the high metastatic potentialcells can be indicative of increased expression of genes or regulatorysequences involved in the metastatic process. A patient sampledisplaying an increased level of one or more of these polynucleotidesmay thus warrant more aggressive treatment. In another example,sequences that display higher expression in the low metastatic potentialcells can be associated with genes or regulatory sequences that inhibitmetastasis, and thus the expression of these polynucleotides in a samplemay warrant a more positive prognosis than the gross pathology wouldsuggest.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic marker, for risk assessment, patienttreatment and the, like. These polynucleotide sequences can also be usedin combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides withdifferential expression between high metastatic potential colon cancercells and low metastatic potential colon cancer cells: TABLE 93Differentially expressed polynucleotides: Higher expression in lowmetastatic colon cancer cells (lib 2) relative to high metastaticpotential colon cancer cells (lib 1) SEQ ID NOs: Lib 1 clones Lib 2clones lib 2/lib 1 10348 0 9 10 11413 0 8 9 11842 34 114 4 11905 3 12 411937 0 9 10 11955 2 10 5 11968 8 25 3 12054 24 87 4 12065 2 16 9 121276 27 5 12134 2 11 6 12158 1 10 11 12226 2 12 6 12232 28 62 2 12276 5 143 12279 3 21 8 12281 0 6 6 12297 3 12 4 12488 3 20 7 12490 0 6 6 1250754 172 3 12511 15 41 3 12530 0 6 6 12555 0 9 10 12560 7 20 3 12569 0 910 12581 0 9 10 12593 4 13 4 12601 0 6 6 12621 9 25 3 12623 8 23 3 126342 12 6 12723 9 22 3 12740 13 29 2 12759 1 8 9 12765 2 15 8 12785 0 6 612825 0 6 6 12834 44 109 3 12852 0 6 6 12854 5 16 3 12876 1 11 12 128783 27 10 12896 16 30 2 12899 12 27 2 12919 2 13 7 12928 12 29 3 13034 0 78 13075 502 2170 5 13129 2 21 11 13130 0 9 10 13132 0 7 8 13154 2 12 613170 2 12 6 13215 3 12 4 13254 1 8 9

Example 62 Polynucleotides Differentially Expressed in High MetastaticPotential Colon Cancer Patient Tissue Versus Normal Patient Tissue

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high metastaticpotential colon cancer tissue and normal tissue. Expression of thesesequences in colon cancer tissue can provide diagnostic, prognosticand/or treatment information. For example, sequences that are highlyexpressed in the high metastatic potential cells can be indicative ofincreased expression of genes or regulatory sequences involved in theadvanced disease state which involves processes such as angiogenesis,differentiation, cell replication, and metastasis. A patient sampledisplaying an increased level of one or more of these polynucleotidesmay thus warrant more aggressive treatment.

The differential expression of these polynucleotides can be used as adiagnostic marker, a prognostic marker, for risk assessment, patienttreatment and the like. These polynucleotide sequences can also be usedin combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentiallyexpressed between high metastatic potential colon cancer tissue andnormal colon tissue: TABLE 94 Differentially expressed polynucleotidesisolated from samples from two patients (patient 2 and patient 3 and):Lower expression in high metastatic potential colon tissue (patient 2:lib 17; patient 3: lib 20) vs. normal colon tissue (patient 2: lib 15;patient 3: lib 18) SEQ ID NO: lib 15 clones lib 17 clones lib 15/lib 17 9988 19 7 3 10042 6 0 6 10059 24 8 3 10116 6 0 6 10117 113 0 121 1017328 9 3 10331 28 9 3 10431 11 1 12 10560 17 7 3 10561 7 0 8 10873 12 3 410930 209 16 14 10943 8 0 9 10959 12 3 4 10974 26 7 4 11025 31 15 211044 17 0 18 11048 17 0 18 11057 109 0 117 11163 14 1 15 11172 73 0 7811202 34 7 5 11204 34 7 5 11258 13 4 3 11393 73 0 78 11424 18 3 6 1147268 6 12 11473 2542 14 195 11524 2542 14 195 11547 6 0 6 11562 142 4 3811672 12 0 10 11683 13 0 14 SEQ ID NO: Lib18 Clones Lib20 Cloneslib18/lib20 10024 28 11 2 10117 21 0 18 10173 9 0 8 10331 9 0 8 10930 111 9 11057 14 0 12 11172 23 0 20 11562 18 0 15 11683 12 0 10 13075 140 433

TABLE 95 Differentially expressed polynucleotides isolated from samplesfrom two patients (patient 2 and patient 3): Lower expression in normalcolon tissue (patient 2: lib 15; patient 3: lib 18)vs. high metastaticpotential colon tissue (patient 2: lib 17; patient 3: lib 20). SEQ IDNO: Lib 15 Clones Lib 17 Clones lib 17/lib 15 10240 3 23 7 10282 1 9 810755 21 99 4 10778 6 20 3 10804 13 28 2 10835 13 28 2 10900 2 11 511145 8 70 8 11227 0 8 7 11236 29 84 3 11348 27 127 4 11361 0 9 8 114531 12 11 11459 12 43 3 11471 0 7 7 11475 1 9 8 11476 1 9 8 11488 21895122 2 11490 6 18 3 11495 3 25 8 11500 4 22 5 11520 25 157 6 11532 9 485 11535 15 61 4 11539 2 17 8 11541 4 99 23 11545 6 35 5 11566 4 22 511583 4 28 7 11602 2 18 8 11623 3 15 5 11719 0 7 7 12668 23 60 2 12703 414 3 12724 1 9 8 12895 3 14 4 13047 18 57 3 13048 26 124 4 13065 64 2103 13069 940 2267 2 13070 2 15 7 SEQ ID NO: lib 18 clones lib 20 cloneslib 20/lib 18 10784 0 5 6 11488 1 7 8 11499 1 7 8 11509 1 7 8 12709 0 56

Example 63 Polynucleotides Differentially Expressed in High Colon TumorPotential Patient Tissue Versus Metastasized Colon Cancer Patient Tissue

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from colon cancer tissueand cells derived from colon cancer tissue metastases to liver.Expression of these sequences in colon cancer tissue can providediagnostic, prognostic and/or treatment information associated with thetransformation of precancerous tissue to malignant tissue. Thisinformation can be useful in the prevention of achieving the advancedmalignant state in these tissues, and can be important in riskassessment for a patient.

The following table summarizes identified polynucleotides withdifferential expression between high tumor potential colon cancer tissueand cells derived from high metastatic potential colon cancer cells:TABLE 96 Differentially expressed polynucleotides: Greater expression inmetastatic colon tumor tissue (lib 20) vs. colon tumor tissue (lib 19)SEQ ID NO: lib 19 clones lib 20 clones lib 20/lib 19 10856 0 6 8 10895 05 7 11439 1 8 11 11465 1 11 15 11469 1 11 15 11493 1 8 11 11499 0 7 911509 0 7 9 11518 8 21 4 11526 158 632 5 11541 1 7 9

TABLE 97 Greater expression in colon tumor tissue (lib 19) thanmetastatic colon tissue (lib 20) SEQ ID NO: lib 19 clones lib 20 cloneslib 19/lib 20 10024 64 11 4 10930 53 1 40 11145 18 4 3 11490 8 0 6 1164515 3 4 11730 17 2 6 12668 47 6 6 13065 19 2 7 13243 20 1 15

Example 64 Polynucleotides Differentially Expressed in High TumorPotential Colon Cancer Patient Tissue Versus Normal Patient Tissue

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from high tumor potentialcolon cancer tissue and normal tissue. Expression of these sequences incolon cancer tissue can provide diagnostic, prognostic and/or treatmentinformation associated with the prevention of the malignant state inthese tissues, and can be important in risk assessment for a patient.For example, sequences that are highly expressed in the potential coloncancer cells are associated with or can be indicative of increasedexpression of genes or regulatory sequences involved in early tumorprogression. A patient sample displaying an increased level of one ormore of these polynucleotides may thus warrant closer attention or morefrequent screening procedures to catch the malignant state as early aspossible.

The following tables summarize polynucleotides that are differentiallyexpressed between high metastatic potential colon cancer cells andnormal colon cells: TABLE 98 Differentially expressed polynucleotidesdetected in samples from patient (patient 2) Higher expression in normalcolon tissue (patient 2, lib 15) vs. tumor potential colon tissue(patient 2: lib 16) SEQ ID NO: lib 15 clones lib 16 clones lib 16/lib 159988 19 7 3 10024 116 54 2 10059 24 4 6 10116 6 0 6 10117 113 3 40 1017328 6 5 10331 28 6 5 10561 7 0 7 10749 10 2 5 10857 31 13 3 10930 209 376 11014 12 3 4 11044 17 0 18 11048 17 0 18 11057 109 1 115 11172 73 1 7711202 34 13 3 11204 34 13 3 11258 13 3 5 11372 11 3 4 11393 73 1 7711424 18 6 3 11473 2542 448 6 11524 2542 448 6 11533 36 14 3 11549 24 93 11562 142 2 75 11565 39 14 3 11568 24 8 3 11596 19 6 3 11672 13 0 1411683 13 0 14 11685 177 65 3 11691 24 8 3

TABLE 99 Differentially expressed polypeptides detected in samples frompatient. Lower expression in normal colon tissue (lib 18) than colontumor tissue (lib 19) SEQ ID NO: lib 18 clones lib 19 clones lib 19/lib18 13065 3 19 6 13069 21 228 10 13243 3 20 6

TABLE 100 Differentially expressed polypeptides detected in samples frompatient. Higher expression in normal colon tissue (lib 18) than colontumor tissue (lib 19) SEQ ID NO: lib 18 clones lib 19 clones lib 18/lib19 10117 21 2 12 10384 6 0 7 10408 6 0 7 10664 6 0 7 10778 11 2 6 108957 0 8 10930 209 37 6 10964 8 1 9 11057 14 0 16 11172 23 0 26 11311 16 45 11393 23 0 26 11508 6 0 7 11510 22 11 2 11526 386 158 3 11562 18 0 2111672 12 0 14 11683 12 0 14 lib 19/lib 18 10024 28 64 2 10930 11 53 411145 2 18 8 11170 6 19 3 11478 1 9 8 11490 0 8 7 11527 1 9 8 11685 2 136 11701 1 9 8 11730 1 17 15

TABLE 101 Differentially expressed polynucleotides: Higher expression incolon tumor tissue (patient 2, lib 16) vs. normal colon tissue (patient2, lib 15) SEQ ID NO: lib 15 clones lib 16 clones lib 16/lib 15 9926 1 99 10083 6 19 3 10653 4 15 4 10755 21 53 2 10847 2 11 5 10884 2 11 510906 2 11 5 10945 7 19 3 10963 4 16 4 11038 4 16 4 11145 8 46 5 11146 09 9 11170 7 95 13 11235 0 6 6 11348 27 81 3 11361 0 9 9 11459 12 28 211472 68 590 8 11479 4 24 6 11496 1 10 9 11507 5 20 4 11529 3 13 4 115392 23 11 11545 6 23 4 11592 2 15 7 12335 0 7 7 12668 23 54 2 12895 3 14 413048 26 64 2 13051 18 54 3

Example 65 Polynucleotides Differentially Expressed in GrowthFactor-Stimulated Human Microvascular Endothelial Cells (HMEC) Relativeto Untreated HMEC

A number of polynucleotide sequences have been identified that aredifferentially expressed between human microvascular endothelial cells(HMEC) that have been treated with growth factors relative to untreatedHMEC.

Sequences that are differentially expressed between growthfactor-treated HMEC and untreated HMEC can represent sequences encodinggene products involved in angiogenesis, metastasis (cell migration), andother developmental and oncogenic processes. For example, sequences thatare more highly expressed in HMEC treated with growth factors (such asbFGF or VEGF) relative to untreated HMEC can serve as markers of cancercells of higher metastatic potential. Detection of expression of thesesequences in colon cancer tissue can provide diagnostic, prognosticand/or treatment information associated with the prevention of achievingthe malignant state in these tissues, and can be important in riskassessment for a patient. A patient sample displaying an increased levelof one or more of these polynucleotides may thus warrant closerattention or more frequent screening procedures to catch the malignantstate as early as possible.

The following table summarizes identified polynucleotides withdifferential expression between growth factor-treated and untreatedHMEC. TABLE 102 Differentially expressed polynucleotides: SEQ ID NO: lib12 clones lib 13 clones lib 12/lib 13 Higher expression in untreatedHMEC (lib 12) vs. bFGF treated HMEC (lib 13) 10768 6 0 6 10978 6 0 611125 12 2 6 13127 12 0 12 Lower expression in untreated HMEC (lib 12)vs. bFGF treated HMEC (lib 13) 12667 3 12 4 13244 0 6 6

TABLE 103 Differentially expressed polynucleotides: SEQ ID NO: lib 12clones lib 14 clones lib 12/lib 14 Higher expression in untreated HMEC(lib 12) VEGF treated HMEC (lib14) 11069 9 0 9 Lower expression inuntreated HMEC (lib 12) vs. VEGF treated HMEC (lib14) 13243 22 50 2

Example 66 Polynucleotides Differentially Expressed in Normal ProstateCells Relative to Prostate Cancer Cells

A number of polynucleotide sequences have been identified that aredifferentially expressed between cells derived from normal prostatecells and prostate cancer cells. Expression of these sequences prostatetissue suspected of being cancerous can provide diagnostic, prognosticand/or treatment information. These polynucleotide sequences can also beused in combination with other known molecular and/or biochemicalmarkers. The following table summarizes identified polynucleotides withdifferential expression between high metastatic potential colon cancercells and low metastatic potential colon cancer cells: TABLE 104Differentially expressed polynucleotides: normal prostate cell line (lib21) vs. prostate cancer cell line (lib 22) SEQ ID NO: lib 21 clones lib22 clones lib 21/lib 22 Higher in lib 21 9972 17 2 8 11673 22 8 3 117207 0 7 11764 22 6 4 10365 8 0 8 11329 6 0 6 11979 18 6 3 12062 12 3 412551 13 1 13 12818 16 2 8 13257 12 2 6 Higher in lib 22 10005 2 13 710012 0 9 9 10606 0 9 9 11188 1 15 15 11500 25 74 3 11566 25 74 3 1156812 27 2 11629 5 16 3 11636 5 16 3 11691 12 27 2 11879 0 6 6 12906 0 6 613047 13 42 3 13051 13 42 3 13069 263 962 4 13141 0 6 6 13187 0 6 6

Example 67 Polynucleotides Differentially Expressed Across MultipleLibraries

A number of polynucleotide sequences have been identified that aredifferentially expressed between cancerous cells and normal cells acrosstwo or more tissue types tested (i.e., breast, colon, lung, andprostate). Expression of these sequences in a tissue of any origin canprovide diagnostic, prognostic and/or treatment information associatedwith the prevention of achieving the malignant state in these tissues,and can be important in risk assessment for a patient. Thesepolynucleotides can also serve as non-tissue specific markers of, forexample, risk of metastasis of a tumor. The following polynucleotideswere differentially expressed but without tissue type-specificity in atleast two of the breast, colon, lung, and prostate libraries tested:9972, 10024, 10274, 10331, 10533, 10755, 11361, 11500, 11566, 11568,11583, 11691, 11701, 11730, 11764, 11775, 11794, 11842, 11979, 11990,12054, 12065, 12158, 12232, 12297, 12312, 12335, 12379, 12409, 12551,12593, 12623, 12643, 12668, 12703, 12723, 12878, 12895, 12896, 12899,12906, 12928, 12966, 13047, 13048, 13051, 13065, 13069, 13075, 13129,13243, 13250 and 13254.

Those skilled in the art will recognize, or be able to ascertain, usingnot more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such specific embodimentsand equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Deposit Information:

The following materials were deposited with the American Type CultureCollection (ATCC); CMCC=Chiron Master Culture Collection: cDNA LibrariesDeposited with ATCC ATCC CMCC Tube Number Deposit Date Accession No.Accession No. ES137 May 30, 2000 ES138 May 30, 2000 ES139 May 30, 2000ES140 May 30, 2000 ES141 May 30, 2000 ES142 May 30, 2000 ES143 May 30,2000 ES137 May 30, 2000 ES144 May 30, 2000 ES145 May 30, 2000 ES146 May30, 2000 ES147 May 30, 2000 ES148 May 30, 2000 ES149 May 30, 2000 ES150May 30, 2000 ES151 May 30, 2000 ES152 May 30, 2000 ES153 May 30, 2000ES154 May 30, 2000 ES155 May 30, 2000 ES156 May 30, 2000 ES157 May 30,2000 ES158 May 30, 2000 ES159 May 30, 2000 ES160 May 30, 2000 ES161 May30, 2000 ES162 May 30, 2000 ES163 May 30, 2000 ES164 May 30, 2000 ES165May 30, 2000 ES166 May 30, 2000 ES167 May 30, 2000

Table 105 lists the clones for each deposit, designated as “tube”number. This deposit is provided merely as convenience to those of skillin the art, and is not an admission that a deposit is required under 35U.S.C. §112. The sequence of the polynucleotides contained within thedeposited material, as well as the amino acid sequence of thepolypeptides encoded thereby, are incorporated herein by reference andare controlling in the event of any conflict with the writtendescription of sequences herein. A license may be required to make, use,or sell the deposited material, and no such license is granted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones

Where the ATCC deposit is composed of a pool of cDNA clones, the depositwas prepared by first transfecting each of the clones into separatebacterial cells. The clones were then deposited as a pool of equalmixtures in the composite deposit. Particular clones can be obtainedfrom the composite deposit using methods well known in the art. Forexample, a bacterial cell containing a particular clone can beidentified by isolating single colonies, and identifying coloniescontaining the specific clone through standard colony hybridizationtechniques, using an oligonucleotide probe or probes designed tospecifically hybridize to a sequence of the clone insert (e.g., a probebased upon unmasked sequence of the encoded polynucleotide having theindicated SEQ ID NO). The probe should be designed to have a T_(m) ofapproximately 80° C. (assuming 2° C. for each A or T and 4° C. for eachG or C). Positive colonies can then be picked, grown in culture, and therecombinant clone isolated. Alternatively, probes designed in thismanner can be used to PCR to isolate a nucleic acid molecule from thepooled clones according to methods well known in the art, e.g., bypurifying the cDNA from the deposited culture pool, and using the probesin PCR reactions to produce an amplified product having thecorresponding desired polynucleotide sequence. TABLE 105 Clone Name TubeM00001351A:B02 ES 137 M00001356A:H11 ES 137 M00001363D:D09 ES 137M00001395D:H02 ES 137 M00001439C:H06 ES 137 M00001476B:G10 ES 137M00001582A:E02 ES 137 M00003750D:E06 ES 137 M00003761C:F02 ES 137M00003770A:E05 ES 137 M00003786A:A11 ES 137 M00003800A:F09 ES 137M00003816D:E11 ES 137 M00003902A:C03 ES 137 M00003991C:F06 ES 137M00003995B:E03 ES 137 M00004046C:A08 ES 137 M00004105D:D05 ES 137M00004139B:B10 ES 137 M00004140D:C03 ES 137 M00004144A:H05 ES 137M00004152A:C12 ES 137 M00004155D:A10 ES 137 M00004168A:G11 ES 137M00004197B:H10 ES 137 M00004222C:E03 ES 137 M00004234A:E07 ES 137M00004239B:F11 ES 137 M00004241B:H07 ES 137 M00004264B:A05 ES 137M00004278A:F09 ES 137 M00004282D:C11 ES 137 M00004308C:C06 ES 137M00004340C:C07 ES 137 M00004354D:E05 ES 137 M00004361A:H02 ES 137M00004372B:F07 ES 137 M00004378A:B10 ES 137 M00004393B:E07 ES 137M00023282A:C02 ES 137 M00023300D:C11 ES 137 M00023316C:G08 ES 137M00023333D:C12 ES 137 M00023352B:F03 ES 137 M00023352D:H03 ES 137M00023376B:G04 ES 137 M00023377B:F01 ES 137 M00023398B:D12 ES 137M00023399C:E10 ES 137 M00026803A:F08 ES 137 M00026843B:D10 ES 137M00026850D:F09 ES 137 M00026851B:F01 ES 137 M00026856D:F02 ES 137M00026857D:G12 ES 137 M00026859D:D01 ES 137 M00026860B:C05 ES 137M00026865B:A06 ES 137 M00026868C:E11 ES 137 M00026878A:F05 ES 137M00026882D:G09 ES 137 M00026885A:H09 ES 137 M00026901A:G07 ES 137M00026914A:H10 ES 137 M00026915B:C06 ES 137 M00026918B:D01 ES 137M00026922C:B02 ES 137 M00026922C:G03 ES 137 M00026926A:E10 ES 137M00026927D:F02 ES 137 M00026928D:A03 ES 137 M00026935C:B04 ES 137M00026941D:A04 ES 137 M00026944B:E03 ES 137 M00026946A:F12 ES 137M00026980A:D09 ES 137 M00027016A:B06 ES 137 M00027018A:C09 ES 137M00027021A:G02 ES 137 M00027022D:G11 ES 137 M00027030C:H06 ES 137M00027035D:C06 ES 137 M00027049B:F05 ES 137 M00027078A:B02 ES 137M00027080A:B01 ES 137 M00027085C:E11 ES 137 M00027094A:B03 ES 137M00027103B:A09 ES 137 M00027108C:B03 ES 137 M00027121D:C05 ES 137M00027135A:B11 ES 137 M00027136C:C09 ES 137 M00027141C:H03 ES 137M00027159D:F03 ES 137 M00027162B:F05 ES 137 M00027178B:G09 ES 137M00027179D:E06 ES 138 M00027181D:A05 ES 138 M00027195C:E04 ES 138M00027198B:B08 ES 138 M00027200A:F02 ES 138 M00027207B:F07 ES 138M00027212D:E03 ES 138 M00027228D:A01 ES 138 M00027232D:B08 ES 138M00027233B:C01 ES 138 M00027236A:E04 ES 138 M00027237C:B08 ES 138M00027248A:C02 ES 138 M00027256B:H09 ES 138 M00027258A:A07 ES 138M00027263A:F10 ES 138 M00027292D:F10 ES 138 M00027297A:C04 ES 138M00027299B:B12 ES 138 M00027301A:G05 ES 138 M00027301B:B08 ES 138M00027314C:D09 ES 138 M00027319D:B11 ES 138 M00027324D:C05 ES 138M00027347C:G07 ES 138 M00027355A:B07 ES 138 M00027359B:G05 ES 138M00027366A:F11 ES 138 M00027379C:B07 ES 138 M00027392B:H02 ES 138M00027396D:G08 ES 138 M00027398C:F07 ES 138 M00027438C:G07 ES 138M00027462A:D07 ES 138 M00027462B:H07 ES 138 M00027468A:C09 ES 138M00027475B:E10 ES 138 M00027476A:C09 ES 138 M00027486A:F06 ES 138M00027520A:C05 ES 138 M00027525B:D06 ES 138 M00027526D:F03 ES 138M00027528C:B10 ES 138 M00027537C:B01 ES 138 M00027546C:B10 ES 138M00027591B:C04 ES 138 M00027596A:A10 ES 138 M00027596C:E06 ES 138M00027602B:C01 ES 138 M00027615A:F10 ES 138 M00027617B:C12 ES 138M00027620D:F11 ES 138 M00027625A:H01 ES 138 M00027634A:D11 ES 138M00027641C:A03 ES 138 M00027647C:D03 ES 138 M00027652B:F11 ES 138M00027668C:H12 ES 138 M00027729D:H06 ES 138 M00027733A:A02 ES 138M00027741B:F09 ES 138 M00027743A:C03 ES 138 M00027801C:C11 ES 138M00027813C:F01 ES 138 M00027818C:C07 ES 138 M00027836D:F12 ES 138M00027837C:D09 ES 138 M00028120D:F12 ES 138 M00028066C:D07 ES 138M00028184D:G10 ES 138 M00028185B:A06 ES 138 M00028196D:A03 ES 138M00028201B:H12 ES 138 M00028207D:E09 ES 138 M00028210B:D02 ES 138M00028212C:B08 ES 138 M00028215D:F03 ES 138 M00028220A:B04 ES 138M00028314D:F05 ES 138 M00028316B:H12 ES 138 M00028354A:B12 ES 138M00028354D:A03 ES 138 M00028357A:G10 ES 138 M00028362A:G11 ES 138M00028364C:G08 ES 138 M00028369D:E08 ES 138 M00028617C:A12 ES 138M00028768C:D05 ES 138 M00028770A:D04 ES 138 M00028772C:B09 ES 138M00028775D:F03 ES 138 M00028777B:G12 ES 138 M00031368A:E10 ES 138M00031417C:G09 ES 138 M00031419D:C04 ES 138 M00031485D:G02 ES 138M00032480B:E10 ES 139 M00032492A:C01 ES 139 M00032495B:D02 ES 139M00032499C:A01 ES 139 M00032508B:H03 ES 139 M00032510D:F12 ES 139M00032510D:G06 ES 139 M00032513D:F01 ES 139 M00032530D:C02 ES 139M00032535D:H01 ES 139 M00032539B:C11 ES 139 M00032540A:A09 ES 139M00032541D:H08 ES 139 M00032545B:H09 ES 139 M00032545D:G05 ES 139M00032550D:C02 ES 139 M00032551B:G05 ES 139 M00032577A:C04 ES 139M00032578A:G06 ES 139 M00032584A:H08 ES 139 M00032592A:H11 ES 139M00032597C:B01 ES 139 M00032638C:G08 ES 139 M00032638D:A06 ES 139M00032668D:G12 ES 139 M00032678C:D06 ES 139 M00032688D:D11 ES 139M00032712B:G02 ES 139 M00032724A:C05 ES 139 M00032725C:F06 ES 139M00032726C:C01 ES 139 M00032731B:C10 ES 139 M00032731C:C07 ES 139M00032737B:E09 ES 139 M00032739A:A06 ES 139 M00032744B:F10 ES 139M00032766B:D12 ES 139 M00032766C:A04 ES 139 M00032790B:A07 ES 139M00032793A:F06 ES 139 M00032797B:G02 ES 139 M00032808B:G10 ES 139M00032811B:D02 ES 139 M00032829B:E06 ES 139 M00032830D:G03 ES 139M00032831C:G07 ES 139 M00032853D:G12 ES 139 M00032864B:B09 ES 139M00032871D:E11 ES 139 M00032876C:D06 ES 139 M00032907A:G04 ES 139M00032909A:B06 ES 139 M00032917D:G09 ES 139 M00032918B:D08 ES 139M00032918B:E06 ES 139 M00032918C:B10 ES 139 M00032921B:H08 ES 139M00032933A:C10 ES 139 M00032939B:E07 ES 139 M00032940A:C02 ES 139M00032942D:C12 ES 139 M00032944B:B02 ES 139 M00032984C:G05 ES 139M00032990B:A11 ES 139 M00032994A:A08 ES 139 M00032995C:C05 ES 139M00033007C:E01 ES 139 M00033019B:E10 ES 139 M00033033C:H01 ES 139M00033034C:A06 ES 139 M00033034C:F02 ES 139 M00033037D:C11 ES 139M00033074A:C08 ES 139 M00033130B:F06 ES 139 M00033140D:F06 ES 139M00033173D:C01 ES 139 M00033176B:E12 ES 139 M00033186C:D11 ES 139M00033189D:F08 ES 139 M00033202D:G06 ES 139 M00033204B:A07 ES 139M00033205A:F03 ES 139 M00033217B:H07 ES 139 M00033218A:C04 ES 139M00033223B:H07 ES 139 M00033226A:A11 ES 139 M00033231D:B09 ES 139M00033231D:G10 ES 139 M00033243B:A05 ES 139 M00033246C:E08 ES 139M00033248A:B02 ES 139 M00033261C:D12 ES 139 M00033262D:A11 ES 139M00033263B:G04 ES 139 M00033276B:G08 ES 139 M00033185C:D01 ES 139M00033288B:D12 ES 140 M00033300D:H12 ES 140 M00033306D:G08 ES 140M00033306D:H09 ES 140 M00033308B:G05 ES 140 M00033343C:H08 ES 140M00033345D:A09 ES 140 M00033346C:A05 ES 140 M00033347C:F02 ES 140M00033349D:F05 ES 140 M00033358A:H12 ES 140 M00033362C:C05 ES 140M00033375A:G04 ES 140 M00033376A:C12 ES 140 M00033377D:A05 ES 140M00033410B:C09 ES 140 M00033424B:A04 ES 140 M00033424D:H12 ES 140M00033425A:C10 ES 140 M00033427D:F01 ES 140 M00033432B:H10 ES 140M00033437C:A07 ES 140 M00033437C:C03 ES 140 M00033442A:D06 ES 140M00033446C:G08 ES 140 M00033446D:B02 ES 140 M00033450C:A02 ES 140M00033451A:H01 ES 140 M00033454A:D09 ES 140 M00033457D:A05 ES 140M00033560D:G07 ES 140 M00033561C:A02 ES 140 M00033566C:E08 ES 140M00033570B:C08 ES 140 M00033570B:E06 ES 140 M00033570C:C10 ES 140M00033578D:G02 ES 140 M00033581C:H10 ES 140 M00033581D:D08 ES 140M00033583B:E06 ES 140 M00033583D:B05 ES 140 M00033584D:G11 ES 140M00033585D:A02 ES 140 M00033588C:G04 ES 140 M00033594C:B03 ES 140M00033595A:C11 ES 140 M00038259A:G08 ES 140 M00038259B:A02 ES 140M00038259B:G08 ES 140 M00038259C:H09 ES 140 M00038272A:G01 ES 140M00038272D:F11 ES 140 M00038279C:A11 ES 140 M00038284B:H04 ES 140M00038303A:C03 ES 140 M00038303C:D02 ES 140 M00038303D:E07 ES 140M00038315C:G11 ES 140 M00038325D:F12 ES 140 M00038326B:D04 ES 140M00038327A:C11 ES 140 M00038327D:A05 ES 140 M00038328D:A03 ES 140M00038329A:E08 ES 140 M00038387B:A07 ES 140 M00038614C:H11 ES 140M00038615A:H12 ES 140 M00038616D:B12 ES 140 M00038618C:C08 ES 140M00038619B:A03 ES 140 M00038620B:E09 ES 140 M00038631C:B10 ES 140M00038631D:B02 ES 140 M00038632C:B09 ES 140 M00038633A:D07 ES 140M00038633B:G02 ES 140 M00038635A:G09 ES 140 M00038635B:C08 ES 140M00038638D:H03 ES 140 M00038639B:C03 ES 140 M00038639D:F07 ES 140M00038661A:A07 ES 140 M00038662B:A12 ES 140 M00038663B:H06 ES 140M00038663D:H10 ES 140 M00038664C:E04 ES 140 M00038991A:D01 ES 140M00038994A:A10 ES 140 M00038995C:G08 ES 140 M00038995D:E05 ES 140M00038999B:G11 ES 140 M00038999D:C11 ES 140 M00039002D:G11 ES 140M00039004B:A06 ES 140 M00039004B:C11 ES 140 M00039005C:H01 ES 141M00039006D:B01 ES 141 M00039011D:C10 ES 141 M00039013A:C09 ES 141M00039013D:F02 ES 141 M00039014A:H10 ES 141 M00039014B:C04 ES 141M00039015A:D07 ES 141 M00039015B:G10 ES 141 M00039015B:H09 ES 141M00039015D:H04 ES 141 M00039016A:A02 ES 141 M00039016D:G06 ES 141M00039024B:B10 ES 141 M00039025A:H09 ES 141 M00039026D:F05 ES 141M00039028C:B11 ES 141 M00039030B:E02 ES 141 M00039036C:B05 ES 141M00039039B:E03 ES 141 M00039039B:F09 ES 141 M00039042B:B02 ES 141M00039043B:E01 ES 141 M00039049D:G07 ES 141 M00039050A:H10 ES 141M00039052C:F07 ES 141 M00039058A:A04 ES 141 M00039058C:H02 ES 141M00039059C:G08 ES 141 M00039061B:F08 ES 141 M00039063B:D08 ES 141M00039064D:H09 ES 141 M00039066D:G08 ES 141 M00039068B:B04 ES 141M00039068C:E06 ES 141 M00039070D:C02 ES 141 M00039072C:C03 ES 141M00039072C:E02 ES 141 M00039079A:A05 ES 141 M00039080C:H06 ES 141M00039081B:G06 ES 141 M00039082B:A05 ES 141 M00039084C:G07 ES 141M00039084C:H03 ES 141 M00039084C:H04 ES 141 M00039084D:D07 ES 141M00039096A:A05 ES 141 M00039096A:E07 ES 141 M00039097D:D06 ES 141M00039099A:H08 ES 141 M00039104D:C09 ES 141 M00039105C:B08 ES 141M00039107C:E04 ES 141 M00039108D:B06 ES 141 M00039112B:C05 ES 141M00039118B:C05 ES 141 M00039118D:A06 ES 141 M00039120C:C09 ES 141M00039120C:H03 ES 141 M00039123A:B10 ES 141 M00039124C:F03 ES 141M00039124C:H02 ES 141 M00039124C:H08 ES 141 M00039126D:A08 ES 141M00039127A:G11 ES 141 M00039127D:E10 ES 141 M00039129C:D04 ES 141M00039133B:F08 ES 141 M00039135D:F05 ES 141 M00039135D:G02 ES 141M00039135D:H02 ES 141 M00039139A:C09 ES 141 M00039139C:G12 ES 141M00039140A:B08 ES 141 M00039140D:A04 ES 141 M00039140D:D09 ES 141M00039141C:E01 ES 141 M00039142D:B11 ES 141 M00039144C:E06 ES 141M00039147A:F10 ES 141 M00039156A:B11 ES 141 M00039158B:G12 ES 141M00039166B:G06 ES 141 M00039167B:H09 ES 141 M00039168C:A04 ES 141M00039169A:E12 ES 141 M00039170A:B10 ES 141 M00039170C:F05 ES 141M00039171B:D11 ES 141 M00039177B:D03 ES 141 M00039179A:G09 ES 141M00039180A:A07 ES 141 M00039196B:H06 ES 141 M00039196D:A07 ES 141M00039200A:C10 ES 141 M00039211A:C12 ES 141 M00039212C:C12 ES 142M00039213A:D01 ES 142 M00039213B:F05 ES 142 M00039218A:F03 ES 142M00039221A:H03 ES 142 M00039224A:E12 ES 142 M00039228A:B05 ES 142M00039230A:A10 ES 142 M00039230D:D09 ES 142 M00039230D:G12 ES 142M00039233A:A03 ES 142 M00039238A:B12 ES 142 M00039238D:A08 ES 142M00039241A:E11 ES 142 M00039249A:C12 ES 142 M00039249C:G11 ES 142M00039255C:E12 ES 142 M00039257D:C03 ES 142 M00039258B:E06 ES 142M00039258D:B08 ES 142 M00039260C:G03 ES 142 M00039263D:A12 ES 142M00039266A:B02 ES 142 M00039266D:F12 ES 142 M00039266D:H04 ES 142M00039273B:F02 ES 142 M00039273D:B02 ES 142 M00039274B:G07 ES 142M00039276B:H09 ES 142 M00039277D:G10 ES 142 M00039279B:C11 ES 142M00039279B:H02 ES 142 M00039279C:B08 ES 142 M00039281D:B04 ES 142M00039284D:B12 ES 142 M00039286A:C06 ES 142 M00039287C:A06 ES 142M00039288C:B11 ES 142 M00039293A:H04 ES 142 M00039293B:C11 ES 142M00039295B:D03 ES 142 M00039297C:H08 ES 142 M00039298B:B06 ES 142M00039298B:D03 ES 142 M00039298D:B04 ES 142 M00039299B:G12 ES 142M00039300C:C09 ES 142 M00039300C:G04 ES 142 M00039301B:F06 ES 142M00039303C:F11 ES 142 M00039304D:B09 ES 142 M00039308B:G08 ES 142M00039310A:C07 ES 142 M00039313D:G04 ES 142 M00039316A:C01 ES 142M00039318B:B09 ES 142 M00039319B:H12 ES 142 M00039319C:A04 ES 142M00039322A:F04 ES 142 M00039328D:D07 ES 142 M00039329A:C01 ES 142M00039329C:B10 ES 142 M00039333D:D09 ES 142 M00039334B:E03 ES 142M00039335A:E08 ES 142 M00039339A:H07 ES 142 M00039339C:F03 ES 142M00039340A:D05 ES 142 M00039340B:E07 ES 142 M00039340B:G08 ES 142M00039341C:H11 ES 142 M00039341D:D07 ES 142 M00039343B:F12 ES 142M00039344B:G07 ES 142 M00039345A:D09 ES 142 M00039345C:C12 ES 142M00039381C:H08 ES 142 M00039381D:C02 ES 142 M00039384C:E02 ES 142M00039384C:F08 ES 142 M00039385B:E09 ES 142 M00039391D:F08 ES 142M00039396D:B04 ES 142 M00039397B:H09 ES 142 M00039398A:B10 ES 142M00039401B:D02 ES 142 M00039402B:E03 ES 142 M00039403A:G12 ES 142M00039404B:A05 ES 142 M00039407B:G02 ES 142 M00039411C:E07 ES 142M00039412D:G06 ES 142 M00039414D:G03 ES 142 M00039415D:E01 ES 142M00039417A:D03 ES 142 M00039417A:E12 ES 142 M00039417B:F01 ES 143M00039417C:A01 ES 143 M00039417C:G01 ES 143 M00039418B:D08 ES 143M00039420D:D03 ES 143 M00039422D:F04 ES 143 M00039425C:G01 ES 143M00039425D:E12 ES 143 M00039428C:E01 ES 143 M00039430B:F12 ES 143M00039431B:F04 ES 143 M00039432C:A01 ES 143 M00039444C:H02 ES 143M00039452C:G09 ES 143 M00039454B:A11 ES 143 M00039455D:H04 ES 143M00039456A:C08 ES 143 M00039458B:H11 ES 143 M00039461A:F04 ES 143M00039465A:A08 ES 143 M00039472C:B08 ES 143 M00039475C:E10 ES 143M00039476B:A02 ES 143 M00039477A:B03 ES 143 M00039477D:A10 ES 143M00039611D:D11 ES 143 M00039612B:B10 ES 143 M00039612B:G05 ES 143M00039616A:B10 ES 143 M00039616B:C01 ES 143 M00039619B:D02 ES 143M00039631A:C10 ES 143 M00039633D:D05 ES 143 M00039636C:D11 ES 143M00039637C:A10 ES 143 M00039652B:D05 ES 143 M00039655B:H09 ES 143M00039655C:C07 ES 143 M00039655C:E08 ES 143 M00039660C:C10 ES 143M00039663C:G09 ES 143 M00039664D:G07 ES 143 M00039672D:D10 ES 143M00039673A:F09 ES 143 M00039675D:B03 ES 143 M00039675D:H05 ES 143M00039677A:B08 ES 143 M00039681B:H09 ES 143 M00039682A:C08 ES 143M00039682C:H11 ES 143 M00039684D:B08 ES 143 M00039685A:A08 ES 143M00039686C:C05 ES 143 M00039686C:E06 ES 143 M00039688C:G06 ES 143M00039689C:E08 ES 143 M00039696A:E05 ES 143 M00039697B:F11 ES 143M00039700B:D02 ES 143 M00039702A:B12 ES 143 M00039702A:B02 ES 143M00039705D:F02 ES 143 M00039707A:D02 ES 143 M00039710C:G03 ES 143M00039720D:D02 ES 143 M00039727C:B09 ES 143 M00039729A:A10 ES 143M00039771C:E11 ES 143 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166M00056220D:G02 ES 166 M00056230D:E07 ES 166 M00056244A:B06 ES 166M00056244C:H05 ES 166 M00056304A:H05 ES 166 M00056320B:A03 ES 166M00056342A:C03 ES 166 M00056345D:A04 ES 166 M00056436C:F01 ES 166M00056458C:E01 ES 166 M00042350A:A05 ES 166 M00042433A:E11 ES 166M00042462B:C02 ES 166 M00042512D:D10 ES 166 M00042766C:D05 ES 166M00042788A:F04 ES 166 M00042794A:F01 ES 166 M00042796A:A10 ES 166M00042801C:D01 ES 166 M00042822A:H04 ES 166 M00042857C:E01 ES 166M00042858C:G11 ES 166 M00042860B:C07 ES 166 M00042863D:F09 ES 166M00042878D:F05 ES 166 M00042878D:G06 ES 166 M00042352B:A04 ES 166M00042352D:B03 ES 166 M00042449B:F05 ES 166 M00042457C:B06 ES 166M00042516B:D01 ES 166 M00042520B:H04 ES 166 M00043299A:B10 ES 166M00043306D:C01 ES 166 M00043313D:E09 ES 166 M00043328C:E04 ES 166M00043336D:B03 ES 166 M00043339C:F11 ES 166 M00043355A:D07 ES 166M00043358C:A02 ES 166 M00043402B:G07 ES 166 M00054499A:C08 ES 166M00054528B:E05 ES 166 M00054536B:B01 ES 166 M00054538D:C12 ES 166M00054542B:A10 ES 166 M00054548C:H06 ES 166 M00054569A:B07 ES 166M00054579A:C02 ES 166 M00054599D:B03 ES 166 M00054623C:F05 ES 166M00054643D:F07 ES 166 M00054675D:G03 ES 166 M00054682B:H02 ES 166M00054683D:G11 ES 166 M00054686A:A09 ES 166 M00054686A:F10 ES 166M00054693A:E11 ES 166 M00054708C:B06 ES 167 M00054714B:G10 ES 167M00054725C:D09 ES 167 M00054744C:F12 ES 167 M00054781B:H04 ES 167M00054781D:A11 ES 167 M00054786C:D08 ES 167 M00054807D:C11 ES 167M00054817D:A11 ES 167 M00054818B:F10 ES 167 M00054843A:C01 ES 167M00054856C:D03 ES 167 M00054866B:C08 ES 167 M00054890C:D05 ES 167M00054908C:A01 ES 167 M00054931D:E10 ES 167 M00054973B:E12 ES 167M00054978C:F01 ES 167 M00055001C:G10 ES 167 M00055002B:E08 ES 167M00055004C:H05 ES 167 M00055023A:E11 ES 167 M00055043B:H08 ES 167M00055055C:F01 ES 167 M00055081A:A05 ES 167 M00055093B:A03 ES 167M00055108B:A02 ES 167 M00055117A:E02 ES 167 M00055166C:D10 ES 167M00055221C:H11 ES 167 M00055232A:E08 ES 167 M00055239D:F11 ES 167M00055240A:A08 ES 167 M00055244B:F07 ES 167 M00055254A:H03 ES 167M00055337B:C04 ES 167 M00055375C:F12 ES 167 M00055387C:C12 ES 167M00055391B:C07 ES 167 M00055395D:D11 ES 167 M00055402A:H01 ES 167M00055420A:E06 ES 167 M00055423A:B08 ES 167 M00055423C:G12 ES 167M00055423C:H10 ES 167 M00055424B:H06 ES 167 M00055424D:G05 ES 167M00055425C:A04 ES 167 M00055473C:F02 ES 167 M00055477D:B01 ES 167M00042585A:H11 ES 167 M00042585D:D03 ES 167 M00042585D:E10 ES 167M00042586A:B01 ES 167 M00042588C:E02 ES 167 M00042621C:C04 ES 167M00042951D:G12 ES 167 M00042960B:C06 ES 167 M00042967D:C01 ES 167M00042970C:B01 ES 167 M00042972C:F04 ES 167 M00042976D:C01 ES 167M00042982D:A10 ES 167 M00042986D:E03 ES 167 M00042996B:H08 ES 167M00043013B:E03 ES 167 M00043015D:D05 ES 167 M00043016B:F09 ES 167M00043017C:D08 ES 167 M00043063C:H05 ES 167 M00043070A:C03 ES 167M00043113C:G09 ES 167 M00042617B:E01 ES 167 M00043074C:D07 ES 167M00043076D:A02 ES 167 M00043077B:F11 ES 167 M00043077C:D12 ES 167M00043077C:G10 ES 167 M00043099A:H04 ES 167 M00043101D:G11 ES 167M00043134A:F05 ES 167 M00043152C:B10 ES 167 M00043213A:D05 ES 167M00043219C:C02 ES 167 M00043221D:C12 ES 167 M00043222C:B06 ES 167M00043455B:C08 ES 167 M00043465C:H11 ES 167 M00043470A:C10 ES 167M00043485C:C03 ES 167 M00043490C:F02 ES 167 M00043495C:H05 ES 167M00043528A:E11 ES 167 M00043529A:B08 ES 167 M00043640A:B01 ES 167

Example 68 Source of Biological Materials and Overview of NovelPolynucleotides Expressed by the Biological Materials

cDNA libraries were constructed from mRNA isolated from the cell linesindicated in Table 109. The specific library from which anypolynucleotide was isolated is indicated in Table 106, with the numberof the entry under the “LIBRARY” column correlating to the librarynumber in Table 109. Polynucleotides expressed by the selected celllines were isolated and analyzed; the sequences of these polynucleotideswere about 275-300 nucleotides in length.

The sequences of the isolated polynucleotides were fist masked toeliminate low complexity sequences using the XBLAST masking program(Claverie “Effective Large-Scale Sequence Similarity Searches,” In:Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed.,Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); seeparticularly Claverie, in “Automated DNA Sequencing and AnalysisTechniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, SanDiego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally,masking does not influence the final search results, except to eliminatesequences of relative little interest due to their low complexity, andto eliminate multiple “hits” based on similarity to repetitive regionscommon to multiple sequences, e.g., Alu repeats. The remaining sequenceswere then used in a BLASTN vs. GenBank search; sequences that exhibitedgreater than 70% overlap, 99% identity, and a p value of less than1×10⁻⁴⁰ were discarded. Sequences from this search also were discardedif the inclusive parameters were met, but the sequence was ribosomal orvector-derived.

The resulting sequences from the previous search were classified intothree groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP(non-redundant proteins) database search: (1) unknown (no hits in theGenBank search), (2) weak similarity (greater than 45% identity and pvalue of less than 1×10⁻⁵), and (3) high similarity (greater than 60%overlap, greater than 80% identity, and p value less than 1×10⁻⁵).Sequences having greater than 70% overlap, greater than 99% identity,and p value of less than 1×10⁻⁴⁰ were discarded.

The remaining sequences were classified as unknown (no hits), weaksimilarity, and high similarity (parameters as above). Two searches wereperformed on these sequences. First, a BLAST vs. EST database search wasperformed and sequences with greater than 99% overlap, greater than 99%similarity and a p value of less than 1×10⁻⁴⁰ were discarded. Sequenceswith a p value of less than 1×10⁻⁶⁵ when compared to a database sequenceof human origin were also excluded. Second, a BLASTN vs. Patent GeneSeqdatabase was performed and sequences having greater than 99% identity, pvalue less than 1×10⁻⁴⁰, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rulesand redundancies in the dataset. Sequences with a p value of less than1×10⁻¹¹¹ in relation to a database sequence of human origin werespecifically excluded. The final result provided the 2396 sequenceslisted as SEQ ID NOS:13271-15666 in the accompanying Sequence Listingand summarized in Table 106. Each identified polynucleotide representssequence from at least a partial mRNA transcript.

Table 106 provides: 1) the SEQ ID NO assigned to each sequence for usein the present specification; 2) the cluster to which the sequence isassigned; 3) the sequence name used as an internal identifier of thesequence; 4) the orientation of the insert in the clone (F=forward;R=reverse); 5) the name assigned to the clone from which the sequencewas isolated; and 6) the library from which the sequence was originallyisolated. Because the provided polynucleotides represent partial mRNAtranscripts, two or more polynucleotides of the invention may representdifferent regions of the same mRNA transcript and the same gene. Thus,if two or more SEQ ID NOS: are identified as belonging to the sameclone, then either sequence can be used to obtain the full-length mRNAor gene.

Example 69 Results of Public Database Search to Identify Function ofGene Products

SEQ ID NOS:13271-15666 were translated in all three reading frames, andthe nucleotide sequences and translated amino acid sequences used asquery sequences to search for homologous sequences in either the GenBank(nucleotide sequences) or Non-Redundant Protein (amino acid sequences)databases. Query and individual sequences were aligned using the BLAST2.0 programs (National Center for Biotechnology Information, Bethesda,Md.; see also Altschul, et al. Nucleic Acids Res. (1997) 25:3389-3402).The sequences were masked to various extents to prevent searching ofrepetitive sequences or poly-A sequences, using the XBLAST program formasking low complexity as described above in Example 68.

Tables 107A and 107B (inserted before the claims) provide the alignmentsummaries having a p value of 1×10⁻² or less indicating substantialhomology between the sequences of the present invention and those of theindicated public databases. Table 107A provides the SEQ ID NO of thequery sequence, the accession number of the GenBank database entry ofthe homologous sequence, and the p value of the alignment. Table 107Bprovides the SEQ ID NO of the query sequence, the accession number ofthe Non-Redundant Protein database entry of the homologous sequence, andthe p value of the alignment. The alignments provided in Tables 107A and107B are the best available alignment to a DNA or amino acid sequence ata time just prior to filing of the present specification. The activityof the polypeptide encoded by the SEQ ID NOS listed in Tables 107A and107B can be extrapolated to be substantially the same or substantiallysimilar to the activity of the reported nearest neighbor or closelyrelated sequence. The accession number of the nearest neighbor isreported, providing a publicly available reference to the activities andfunctions exhibited by the nearest neighbor. The public informationregarding the activities and functions of each of the nearest neighborsequences is incorporated by reference in this application. Alsoincorporated by reference is all publicly available informationregarding the sequence, as well as the putative and actual activitiesand functions of the nearest neighbor sequences listed in Table 107B andtheir related sequences. The search program and database used for thealignment, as well as the calculation of the p value are also indicated.

Full length sequences or fragments of the polynucleotide sequences ofthe nearest neighbors can be used as probes and primers to identify andisolate the full length sequence of the corresponding polynucleotide.The nearest neighbors can indicate a tissue or cell type to be used toconstruct a library for the full-length sequences of the correspondingpolynucleotides.

Example 70 Members of Protein Families

SEQ ID NOS: 13271-15666 were used to conduct a profile search asdescribed in the specification above. Several of the polynucleotides ofthe invention were found to encode polypeptides having characteristicsof a polypeptide belonging to a known protein family (and thus representnmembers of these protein families) and/or comprising a known functionaldomain. Table provides the SEQ ID NO: of the query sequence, the profilename, and a brief description of the profile hit. TABLE 108 SEQ IDProfilename Description 13680 ATPases ATPases Associated with VariousCellular Activities 13807 ATPases ATPases Associated with VariousCellular Activities 13809 ATPases ATPases Associated with VariousCellular Activities 13810 ATPases ATPases Associated with VariousCellular Activities 13932 rrm RNA recognition motif. (aka RRM, RBD orRNP domain) 13953 rrm RNA recognition motif. (aka RRM, RBD, or RNPdomain) 13977 dualspecphosphatase Dual specificity phosphatase,catalytic domain 13978 rrm RNA recognition motif. (aka RRM, RBD, or RNPdomain) 13989 EFhand EF-hand 14008 ATPases ATPases Associated withVarious Cellular Activities 14049 Zincfing_C2H2 Zinc finger, C2H2 type14051 rrm RNA recognition motif. (aka RRM, RBD, or RNP domain) 14053 rrmRNA recognition motif. (aka RRM, RBD, or RNP domain) 14380 WD_domain WDdomain, G-beta repeats 14685 Dead_box_helic DEAD and DEAH box helicases14803 C2 C2 domain (prot. kinase C like) 14903 dualspecphosphatase Dualspecificity phosphatase, catalytic domain 14907 Dead_box_helic DEAD andDEAH box helicases 14908 Dead_box_helic DEAD and DEAH box helicases15014 WD_domain WD domain, G-beta repeats 15029 BZIP Basic region plusleucine zipper transcription factors 15263 WD_domain WD domain, G-betarepeats 15353 WD_domain WD domain, G-beta repeats 15479 ATPases ATPasesAssociated with Various Cellular Activities 15498 ras Ras family 15557ras Ras family 15570 neur_chan Neurotransmitter-gated ion-channel 15572tor_domain2 kinase domain of tors (Christoph Reinhard) 15576 homeoboxHomeobox Domain 15588 Metallothion Metallothioneins 15597 asp Eukaryoticaspartyl proteases

Some polynucleotides exhibited multiple profile hits where the querysequence contains overlapping profile regions, and/or where the sequencecontains two different functional domains. Each of the profile hits ofTable 108 are described in more detail below. The acronyms for theprofiles (provided in parentheses) are those used to identify theprofile in the Pfam and Prosite databases. The Pfam database can beaccessed through web sites supported by the Washington University, St.Louis (Mo.), The Sanger Centre (United Kingdom); and The KarolinskaInstitute Center for Genomics Research. The Prosite database ispublicaly available through the ExPASy Molecular Biology Server. Thepublic information available on the Pfam and Prosite databases regardingthe various profiles, including but not limited to the activities,function, and consensus sequences of various proteins families andprotein domains, is incorporated herein by reference.

Eukaryotic Aspartyl Proteases (asp; Pfam Accession No. PF00026). One SEQID NO corresponds to a gene encoding a novel eukaryotic aspartylprotease. Aspartyl proteases, known as acid proteases, (EC 3.4.23.-) area widely distributed family of proteolytic enzymes (Foltmann B., EssaysBiochem. (1981) 17:52; Davies D. R., Annu. Rev. Biophys. Chem. (1990)19:189; Rao J. K. M., et al., Biochemistry (1991) 30:4663) known toexist in vertebrates, fungi, plants, retroviruses and some plantviruses. Aspartate proteases of eukaryotes are monomeric enzymes whichconsist of two domains.

ATPases Associated with Various Cellular Activities (ATPases; PfamAccession No. PF0004). Some SEQ ID NOS correspond to a sequence thatencodes a member of a family of ATPases Associated with diverse cellularActivities (AAA). The AAA protein family is composed of a large numberof ATPases that share a conserved region of about 220 amino acidscontaining an ATP-binding site (Froehlich et al., J. Cell Biol. (1991)114:443; Erdmann et al. Cell (1991) 64:499; Peters et al., EMBO J.(1990) 9:1757; Kunau et al., Biochimie (1993) 75:209-224; Confalonieriet al., BioEssays (1995) 17:639; see also the AAA Server Homepage). TheAAA domain, which can be present in one or two copies, acts as anATP-dependent protein clamp (Confalonieri et al. (1995) BioEssays17:639) and contains a highly conserved region located in the centralpart of the domain.

Basic Region Plus Leucine Zipper Transcription Factors (BZIP; PfamAccession No. PF00170). One SEQ ID NO represents a polynucleotideencoding a novel member of the family of basic region plus leucinezipper transcription factors. The bZIP superfamily (Hurst, Protein Prof.(1995) 2:105; and Ellenberger, Curr. Opin. Struct. Biol. (1994) 4:12) ofeukaryotic DNA-binding transcription factors encompasses proteins thatcontain a basic region mediating sequence-specific DNA-binding followedby a leucine zipper required for dimerization.

C2 domain (C2; Pfam Accession No. PF00168). ONe SEQ ID NO corresponds toa sequence encoding a C2 domain, which is involved in calcium-dependentphospholipid binding (Davletov J. Biol. Chem. (1993) 268:26386-26390)or, in proteins that do not bind calcium, the domain may facilitatebinding to inositol-1,3,4,5-tetraphosphate (Fukuda et al. J. Biol. Chem.(1994) 269:29206-29211; Sutton et al. Cell (1995) 80:929-938).

DEAD and DEAH box families ATP-dependent helicases (Dead_box_helic; PfamAccession No. PF00270). Some SEQ ID NOS represent polynucleotidesencoding a novel member of the DEAD and DEAH box families (Schmid etal., Mol. Microbiol. (1992) 6:283; Linder et al., Nature (1989) 337:121;Wassarman, et al., Nature (1991) 349:463). All members of these familiesare involved in ATP-dependent, nucleic-acid unwinding. All DEAD boxfamily members share a number of conserved sequence motifs, some ofwhich are specific to the DEAD family, with others shared by otherATP-binding proteins or by proteins belonging to the helicases‘superfamily’ (Hodgman Nature (1988) 333:22 and Nature (1988) 333:578(Errata)). One of these motifs, called the ‘D-E-A-D-box’, represents aspecial version of the B motif of ATP-binding proteins. Proteins thathave His instead of the second Asp and are ‘D-E-A-H-box’ proteins(Wassarman et al., Nature (1991) 349:463; Harosh, et al., Nucleic AcidsRes. (1991) 19:6331; Koonin, et al., J. Gen. Virol. (1992) 73:989).

Dual specificity phosphatase (DSPc; Pfam Accession No. PF00782). SomeSEQ ID NOS correspond to sequences that encode members of a family ofdual specificity phosphatases (DSPs). DSPs are Ser/Thr and Tyr proteinphosphatases that comprise a tertiary fold highly similar to that oftyrosine-specific phosphatases, except for a “recognition” regionconnecting helix alpha1 to strand beta1. This tertiary fold maydetermine differences in substrate specific between VH-1 related dualspecificity phosphatase (VHR), the protein tyrosine phosphatases (PTPs),and other DSPs. Phosphatases are important in the control of cellgrowth, proliferation, differentiation and transformation.

EF Hand (Efhand; Pfam Accession No. PF00036). One SEQ ID NO correspondsto a polynucleotide encoding a member of the EF-hand protein family, acalcium binding domain shared by many calcium-binding proteins belongingto the same evolutionary family (Kawasaki et al., Protein. Prof. (1995)2:305-490). The domain is a twelve residue loop flanked on both sides bya twelve residue alpha-helical domain, with a calcium ion coordinated ina pentagonal bipyramidal configuration. The six residues involved in thebinding are in positions 1, 3, 5, 7, 9 and 12; these residues aredenoted by X, Y, Z, −Y, −X and −Z. The invariant Glu or Asp at position12 provides two oxygens for liganding Ca (bidentate ligand).

Homeobox domain (homeobox; Pfam Accession No. PF00046). One SEQ ID NOrepresents a polynucleotide encoding a protein having a homeobox domain.The ‘homeobox’ is a protein domain of 60 amino acids (Gehring In:Guidebook to the Homebox Genes, Duboule D., Ed., pp1-10, OxfordUniversity Press, Oxford, (1994); Buerglin In: Guidebook to the HomeboxGenes, pp25-72, Oxford University Press, Oxford, (1994); Gehring TrendsBiochem. Sci. (1992) 17:277-280; Gehring et al Annu. Rev. Genet. (1986)20:147-173; Schofield Trends Neurosci. (1987) 10:3-6) first identifiedin number of Drosophila homeotic and segmentation proteins. It isextremely well conserved in many other animals, including vertebrates.This domain binds DNA through a helix-turn-helix type of structure.Several proteins that contain a homeobox domain play an important rolein development. Most of these proteins are sequence-specific DNA-bindingtranscription factors. The homeobox domain is also very similar to aregion of the yeast mating type proteins. These are sequence-specificDNA-binding proteins that act as master switches in yeastdifferentiation by controlling gene expression in a cell type-specificfashion.

A schematic representation of the homeobox domain is shown below. Thehelix-turn-helix region is shown by the symbols ‘H’ (for helix), and ‘t’(for turn).

The pattern detects homeobox sequences 24 residues long and spanspositions 34 to 57 of the homeobox domain.

Metallothioneins (metalthio; Pfam Accession No. PF00131). One SEQ ID NOcorresponds to a polynucleotide encoding a member of the metallothionein(MT) protein family (Hamer Annu. Rev. Biochem. (1986) 55:913-951; andKagi et al. Biochemistry (1988) 27:8509-8515), small proteins which bindheavy metals such as zinc, copper, cadmium, nickel, etc., throughclusters of thiolate bonds. MT's occur throughout the animal kingdom andare also found in higher plants, fungi and some prokaryotes. On thebasis of structural relationships MT's have been subdivided into threeclasses. Class I includes mammalian MT's as well as MT's from crustaceanand molluscs, but with clearly related primary structure. Class IIgroups together MT's from various species such as sea urchins, fungi,insects and cyanobacteria which display none or only very distantcorrespondence to class I MT's. Class III MT's are atypical polypeptidescontaining gamma-glutamylcysteinyl units.

Neurotransmitter-Gated Ion-Channel (neur_chan; Pfam Accession No.PF00065). One SEQ ID NO corresponds to a sequence encoding aneurotransmitter-gated ion channel. Neurotransmitter-gated ion-channels,which provide the molecular basis for rapid signal transmission atchemical synapses, are post-synaptic oligomeric transmembrane complexesthat transiently form a ionic channel upon the binding of a specificneurotransmitter. Five types of neurotransmitter-gated receptors areknown: 1) nicotinic acetylcholine receptor (AchR); 2) glycine receptor;3) gamma-aminobutyric-acid (GABA) receptor; 4) serotonin 5HT3 receptor;and 5) glutamate receptor. All known sequences of subunits fromneurotransmitter-gated ion-channels are structurally related, and arecomposed of a large extracellular glycosylated N-terminal ligand-bindingdomain, followed by three hydrophobic transmembrane regions that formthe ionic channel, followed by an intracellular region of variablelength. A fourth hydrophobic region is found at the C-terminal of thesequence.

Ras family proteins (ras; Pfam Accession No. PF00071). Some SEQ ID NOSrepresent polynucleotides encoding the ras family of smallGTP/GDP-binding proteins (Valencia et al., 1991, Biochemistry30:4637-4648). Ras family members generally require a specific guaninenucleotide exchange factor (GEF) and a specific GTPase activatingprotein (GAP) as stimulators of overall GTPase activity. Amongras-related proteins, the highest degree of sequence conservation isfound in four regions that are directly involved in guanine nucleotidebinding. The first two constitute most of the phosphate and Mg2+ bindingsite (PM site) and are located in the first half of the G-domain. Theother two regions are involved in guanosine binding and are located inthe C-terminal half of the molecule. Motifs and conserved structuralfeatures of the ras-related proteins are described in Valencia et al.,1991, Biochemistry 30:4637-4648.

RNA Recognition Motif (rrm; Pfam Accession No. PF00076). Some SEQ ID NOScorrespond to sequence encoding an RNA recognition motif, also known asan RRM, RBD, or RNP domain. This domain, which is about 90 amino acidslong, is contained in eukaryotic proteins that bind single-stranded RNA(Bandziulis et al. Genes Dev. (1989) 3:431-437; Dreyfuss et al. TrendsBiochem. Sci. (1988) 13:86-91). Two regions within the RNA-bindingdomain are highly conserved: the first is a hydrophobic segment of sixresidues (which is called the RNP-2 motif), the second is an octapeptidemotif (which is called RNP-1 or RNP-CS).

Kinase Domain of Tors (tor_domain2). One SEQ ID NO corresponds to amember of the TOR lipid kinase protein family. This family is composedof large proteins with a lipid and protein kinase domain andcharacterized through their sensitivity to rapamycin (an antifungalcompound). TOR proteins are involved in signal transduction downstreamof PI3 kinase and many other signals. TOR (also called FRAP, RAFT) playsa role in regulating protein synthesis and cell growth, and in yeastcontrols translation initiation and early G1 progression. See, e.g.,Barbet et al. Mol Biol Cell. (1996) 7(1):25-42; Helliwell et al.Genetics (1998) 148:99-112.

WD Domain, G-Beta Repeats (WD_domain: Pfam Accession No. PF00400). SomeSEQ ID NOS represent novel members of the WD domain/G-beta repeatfamily. Beta-transducin (G-beta) is one of the three subunits (alpha,beta, and gamma) of the guanine nucleotide-binding proteins (G proteins)which act as intermediaries in the transduction of signals generated bytransmembrane receptors (Gilman, Annu. Rev. Biochem. (1987) 56:615). Thealpha subunit binds to and hydrolyzes GTP; the functions of the beta andgamma subunits are less clear but they seem to be required for thereplacement of GDP by GTP as well as for membrane anchoring and receptorrecognition. In higher eukaryotes, G-beta exists as a small multigenefamily of highly conserved proteins of about 340 amino acid residues.Structurally, G-beta consists of eight tandem repeats of about 40residues, each containing a central Trp-Asp motif (this type of repeatis sometimes called a WD-40 repeat).

Zinc Finger, C2H2 Type (Zincfing C2H2; Pfam Accession No. PF00096). OneSEQ ID NO corresponds to a polynucleotid encoding a member of the C2H2type zinc finger protein family, which contain zinc finger domains thatfacilitate nucleic acid binding (Klug et al., Trends Biochem. Sci.(1987) 12:464; Evans et al., Cell (1988) 52:1; Payre et al., FEBS Lett.(1988) 234:245; Miller et al., EMBO J. (1985) 4:1609; and Berg, Proc.Natl. Acad. Sci. USA (1988) 85:99).

In addition to the conserved zinc ligand residues, a number of otherpositions are also important for the structural integrity of the C2H2zinc fingers. (Rosenfeld et al., J. Biomol. Struct. Dyn. (1993) 11:557)The best conserved position, which is generally an aromatic or aliphaticresidue, is located four residues after the second cysteine.

Example 71 Differential Expression of Polynucleotides of the Invention:Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the inventionwas assessed in several libraries prepared from various sources,including cell lines and patient tissue samples. Table 109 provides asummary of these libraries, including the shortened library name (usedhereafter), the mRNA source used to prepared the cDNA library, and theapproximate number of clones in the library. TABLE 109 Description ofcDNA Libraries Number of Library Clones in (Lib#) Description Library 1Human Colon Cell Line Km12 L4: High Metastatic 308731 Potential (derivedfrom Km12C) 2 Human Colon Cell Line Km12C: Low Metastatic Potential284771 3 Human Breast Cancer Cell Line MDA-MB-231: High 326937Metastatic Potential; micro-mets in lung 4 Human Breast Cancer Cell LineMCF7: Non Metastatic 318979 8 Human Lung Cancer Cell Line MV-522: HighMetastatic 223620 Potential 9 Human Lung Cancer Cell Line UCP-3: LowMetastatic 312503 Potential 12 Human microvascular endothelial cells(HMVEC) - 41938 UNTREATED (PCR (OligodT) cDNA library) 13 Humanmicrovascular endothelial cells (HMVEC) - bFGF 42100 TREATED (PCR(OligodT) cDNA library) 14 Human microvascular endothelial cells(HMVEC) - VEGF 42825 TREATED (PCR (OligodT) cDNA library) 15 NormalColon - UC#2 Patient (MICRODISSECTED PCR 282722 (OligodT) cDNA library)16 Colon Tumor - UC#2 Patient (MICRODISSECTED PCR 298831 (OligodT) cDNAlibrary) 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467(MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3Patient (MICRODISSECTED PCR 36216 (OligodT) cDNA library) 19 ColonTumor - UC#3 Patient (MICRODISSECTED PCR 41388 (OligodT) cDNA library)20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956(MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived fromnormal prostate epithelium 164801 22 WOca Cells derived from GleasonGrade 4 prostate cancer 162088 epithelium 23 Normal Lung Epithelium ofPatient #1006 306198 (MICRODISSECTED PCR (OligodT) cDNA library) 24Primary tumor, Large Cell Carcinoma of Patient #1006 309349(MICRODISSECTED PCR (OligodT) cDNA library)

The KM12L4 cell line (Morikawa, et al., Cancer Research (1988) 48:6863)is derived from the KM12C cell line (Morikawa et al. Cancer Res. (1988)48:1943-1948). The KM12C cell line, which is poorly metastatic (lowmetastatic) was established in culture from a Dukes' stage B₂ surgicalspecimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KM12L4-A is ahighly metastatic subline derived from KM12C (Yeatman et al. Nucl.Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc.Cancer Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines(e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a modelcell line for the study of colon cancer (see, e.g., Moriakawa et al.,supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al.,(1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246). TheMDA-MB-231 cell line was originally isolated from pleural effusions(Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastaticpotential, and forms poorly differentiated adenocarcinoma grade II innude mice consistent with breast carcinoma. The MCF7 cell line wasderived from a pleural effusion of a breast adenocarcinoma and isnon-metastatic. The MDA-MB-231 and MCF-7 cell lines are well-recognizedin the art as a models for the study of human breast cancer (see, e.g.,Chandrasekaran et al., Cancer Res. (1979) 39:870; Gastpar et al., J MedChem (1998) 41:4965; Ranson et al., Br J Cancer (1998) 77:1586; andKuang et al., Nucleic Acids Res (1998) 26:1116).

The MV-522 cell line is derived from a human lung carcinoma and is ofhigh metastatic potential. The UCP-3 cell line is a low metastatic humanlung carcinoma cell line; the MV-522 is a high metastatic variant ofUCP-3. These cell lines are well-recognized in the art as models for thestudy of human lung cancer (see, e.g., Varki et al., Int J Cancer (1987)40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 andUCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner etal., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., AnticancerDrugs (1997) 8:696 (MV522)). The samples of libraries 15-20 are derivedfrom two different patients (UC#2, and UC#3). The bFGF-treated HMVECwere prepared by incubation with bFGF at 10 ng/ml for 2 hrs; theVEGF-treated HMVEC were prepared by incubation with 20 ng/ml VEGF for 2hrs. Following incubation with the respective growth factor, the cellswere washed and lysis buffer added for RNA preparation. The GRRpz andWOca cell lines were provided by Dr. Donna M. Peehl, Department ofMedicine, Stanford University School of Medicine. GRRpz was derived fromnormal prostate epithelium. The WOca cell line is a Gleason Grade 4 cellline.

Each of the libraries is composed of a collection of cDNA clones that inturn are representative of the mRNAs expressed in the indicated mRNAsource. In order to facilitate the analysis of the millions of sequencesin each library, the sequences were assigned to clusters. The concept of“cluster of clones” is derived from a sorting/grouping of cDNA clonesbased on their hybridization pattern to a panel of roughly 300 7 bpoligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29).Random cDNA clones from a tissue library are hybridized at moderatestringency to 300 7 bp oligonucleotides. Each oligonucleotide has somemeasure of specific hybridization to that specific clone. Thecombination of 300 of these measures of hybridization for 300 probesequals the “hybridization signature” for a specific clone. Clones withsimilar sequence will have similar hybridization signatures. Bydeveloping a sorting/grouping algorithm to analyze these signatures,groups of clones in a library can be identified and brought togethercomputationally. These groups of clones are termed “clusters”. Dependingon the stringency of the selection in the algorithm (similar to thestringency of hybridization in a classic library cDNA screeningprotocol), the “purity” of each cluster can be controlled. For example,artifacts of clustering may occur in computational clustering just asartifacts can occur in “wet-lab” screening of a cDNA library with 400 bpcDNA fragments, at even the highest stringency. The stringency used inthe implementation of cluster herein provides groups of clones that arein general from the same cDNA or closely related cDNAs. Closely relatedclones can be a result of different length clones of the same cDNA,closely related clones from highly related gene families, or splicevariants of the same cDNA.

Differential expression for a selected cluster was assessed by firstdetermining the number of cDNA clones corresponding to the selectedcluster in the first library (Clones in 1^(st)), and the determining thenumber of cDNA clones corresponding to the selected cluster in thesecond library (Clones in 2^(nd)). Differential expression of theselected cluster in the first library relative to the second library isexpressed as a “ratio” of percent expression between the two libraries.In general, the “ratio” is calculated by: 1) calculating the percentexpression of the selected cluster in the first library by dividing thenumber of clones corresponding to a selected cluster in the firstlibrary by the total number of clones analyzed from the first library;2) calculating the percent expression of the selected cluster in thesecond library by dividing the number of clones corresponding to aselected cluster in a second library by the total number of clonesanalyzed from the second library; 3) dividing the calculated percentexpression from the first library by the calculated percent expressionfrom the second library. If the “number of clones” corresponding to aselected cluster in a library is zero, the value is set at 1 to aid incalculation. The formula used in calculating the ratio takes intoaccount the “depth” of each of the libraries being compared, i.e., thetotal number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentiallyexpressed between two samples when the ratio value is greater than atleast about 2, preferably greater than at least about 3, more preferablygreater than at least about 5, where the ratio value is calculated usingthe method described above. The significance of differential expressionis determined using a z score test (Zar, Biostatistical Analysis,Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298(1974).

Example 72 Differential Expression of Genes Corresponding toPolynucleotides of the Invention

A number of polynucleotide sequences have been identified that aredifferentially expressed between, for example, cells derived from highmetastatic potential cancer tissue and low metastatic cancer cells, andbetween cells derived from metastatic cancer tissue and normal tissue.Evaluation of the levels of expression of the genes corresponding tothese sequences can be valuable in diagnosis, prognosis, and/ortreatment (e.g., to facilitate rationale design of therapy, monitoringduring and after therapy, etc.). Moreover, the genes corresponding todifferentially expressed sequences described herein can be therapeutictargets due to their involvement in regulation (e.g., inhibition orpromotion) of development of, for example, the metastatic phenotype. Forexample, sequences that correspond to genes that are increased inexpression in high metastatic potential cells relative to normal ornon-metastatic tumor cells may encode genes or regulatory sequencesinvolved in processes such as angiogenesis, differentiation, cellreplication, and metastasis.

Detection of the relative expression levels of differentially expressedpolynucleotides described herein can provide valuable information toguide the clinician in the choice of therapy. For example, a patientsample exhibiting an expression level of one or more of thesepolynucleotides that corresponds to a gene that is increased inexpression in metastatic or high metastatic potential cells may warrantmore aggressive treatment for the patient. In contrast, detection ofexpression levels of a polynucleotide sequence that corresponds toexpression levels associated with that of low metastatic potential cellsmay warrant a more positive prognosis than the gross pathology wouldsuggest.

The differential expression of the polynucleotides described herein canthus be used as, for example, diagnostic markers, prognostic markers,for risk assessment, patient treatment and the like. Thesepolynucleotide sequences can also be used in combination with otherknown molecular and/or biochemical markers. The following examplesprovide relative expression levels of polynucleotides from specifiedcell lines and patient tissue samples.

The differential expression data for polynucleotides of the inventionthat have been identified as being differentially expressed acrossvarious combinations of the libraries described above is summarized inTable 110 (inserted prior to the claims). Table 110 provides: 1) theSequence Identification Number (“SEQ”) assigned to the polynucleotide;2) the cluster (“CLST”) to which the polynucleotide has been assigned asdescribed above; 3) the library comparisons that resulted inidentifcation of the polynucleotide as being differentially expressed(“Library Pair A,B”), with shorthand names of the compared librariesprovided in parentheses following the library numbers; 4) the number ofclones corresponding to the polynucleotide in the first library listed(“A”); 5) the number of clones corresponding to the polynucleotide inthe second library listed (“B”); 6) the “A/B” where the comparisonresulted in a finding that the number of clones in library A is greaterthan the number of clones in library B; and 7) the “B/A” where thecomparison resulted in a finding that the number of clones in library Bis greater than the number of clones in library A.

Example 73 Source of Biological Materials for Microarray-BasedExperiments

The biological materials used in the experiments described in thesubsequent examples relating to microarry data are described below.

Source of Patient Tissue Samples

Normal and cancerous tissues were collected from patients using lasercapture microdissection (LCM) techniques, which techniques are wellknown in the art (see, e.g., Ohyama et al. (2000) Biotechniques29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al.(1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Bucket al. (1996) Science 274:998-1001). Table 114 provides informationabout each patient from which the samples were isolated, including: thePatient ID and Path ReportID, numbers assigned to the patient and thepathology reports for identification purposes; the anatomical locationof the tumor (AnatomicalLoc); The Primary Tumor Size; the Primary TumorGrade; the Histopathologic Grade; a description of local sites to whichthe tumor had invaded (Local Invasion); the presence of lymph nodemetastases (Lymph Node Metastasis); incidence of lymph node metastases(provided as number of lymph nodes positive for metastasis over thenumber of lymph nodes examined) (Incidence Lymphnode Metastasis); theRegional Lymphnode Grade; the identification or detection of metastasesto sites distant to the tumor and their location (Distant Met & Loc); adescription of the distant metastases (Description Distant Met); thegrade of distant metastasis (Distant Met Grade); and general commentsabout the patient or the tumor (Comments). Adenoma was not described inany of the patients. adenoma dysplasia (described as hyperplasia by thepathologist) was described in Patient ID No. 695. Extranodal extensionswere described in two patients, Patient ID Nos. 784 and 791.Lymphovascular invasion was described in seven patients, Patient ID Nos.128, 278, 517, 534, 784, 786, and 791. Crohn's-like infiltrates weredescribed in seven patients, Patient ID Nos. 52, 264, 268, 392, 393,784, and 791.

Polynucleotides on Arrays

Polynucleotides spotted on the arrays were generated by PCRamplification of clones derived from cDNA libraries. The clones used foramplification were either the clones from which the sequences describedherein (SEQ ID NOS: 13271-15666) were derived, or are clones havinginserts with significant polynucleotide sequence overlap wih thesequences described herein (SEQ ID NO: 13271-15666) as determined byBLAST2 homology searching.

Example 74 Microarray Design

Each array used in the examples below had an identical spatial layoutand control spot set. Each microarray was divided into two areas, eacharea having an array with, on each half, twelve groupings of 32×12 spotsfor a total of about 9,216 spots on each array. The two areas arespotted identically which provide for at least two duplicates of eachclone per array. Spotting was accomplished using PCR amplified productsfrom 0.5 kb to 2.0 kb and spotted using a Molecular Dynamics Gen IIIspotter according to the manufacturer's recommendations. The first rowof each of the 24 regions on the array had about 32 control spots,including 4 negative control spots and 8 test polynucleotides.

The test polynucleotides were spiked into each sample before thelabeling reaction with a range of concentrations from 2-600 pg/slide andratios of 1:1. For each array design, two slides were hybridized withthe test samples reverse-labeled in the labeling reaction. This providedfor about 4 duplicate measurements for each clone, two of one color andtwo of the other, for each sample.

Example 75 Identification of Differentially Expressed Genes

cDNA probes were prepared from total RNA isolated from the patient cellsdescribed in Example 6. Since LCM provides for the isolation of specificcell types to provide a substantially homogenous cell sample, thisprovided for a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primercontaining a T7 RNA polymerase promoter, followed by second strand DNAsynthesis. cDNA was then transcribed in vitro to produce antisense RNAusing the T7 promoter-mediated expression (see, e.g., Luo et al. (1999)Nature Med 5:117-122), and the antisense RNA was then converted intocDNA. The second set of cDNAs were again transcribed in vitro, using theT7 promoter, to provide antisense RNA. Optionally, the RNA was againconverted into cDNA, allowing for up to a third round of T7-mediatedamplification to produce more antisense RNA. Thus the procedure providedfor two or three rounds of in vitro transcription to produce the finalRNA used for fluorescent labeling. Fluorescent probes were generated byfirst adding control RNA to the antisense RNA mix, and producingfluorescently labeled cDNA from the RNA starting material. Fluorescentlylabeled cDNAs prepared from the tumor RNA sample were compared tofluorescently labeled cDNAs prepared from normal cell RNA sample. Forexample, the cDNA probes from the normal cells were labeled with Cy3fluorescent dye (green) and the cDNA probes prepared from the tumorcells were labeled with Cy5 fluorescent dye (red).

The differential expression assay was performed by mixing equal amountsof probes from tumor cells and normal cells of the same patient. Thearrays were prehybridized by incubation for about 2 hrs at 60° C. in5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twicein isopropanol. Following prehybridization of the array, the probemixture was then hybridized to the array under conditions of highstringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS.After hybridization, the array was washed at 55° C. three times asfollows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2%SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using aMolecular Dynamics Generation III dual color laser-scanner/detector. Theimages were processed using BioDiscovery Autogene software, and the datafrom each scan set normalized to provide for a ratio of expressionrelative to normal. Data from the microarray experiments was analyzedaccording to the algorithms described in U.S. application Ser. No.60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M.Randazzo, and entitled “Precision and accuracy in cDNA microarray data,”which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with theopposite color in order to perform the assay in both “color directions.”Each experiment was sometimes repeated with two more slides (one in eachcolor direction). The level fluorescence for each sequence on the arrayexpressed as a ratio of the geometric mean of 8 replicate spots/genesfrom the four arrays or 4 replicate spots/gene from 2 arrays or someother permutation. The data were normalized using the spiked positivecontrols present in each duplicated area, and the precision of thisnormalization was included in the final determination of thesignificance of each differential. The fluorescent intensity of eachspot was also compared to the negative controls in each duplicated areato determine which spots have detected significant expression levels ineach sample.

A statistical analysis of the fluorescent intensities was applied toeach set of duplicate spots to assess the precision and significance ofeach differential measurement, resulting in a p-value testing the nullhypothesis that there is no differential in the expression level betweenthe tumor and normal samples of each patient. During initial analysis ofthe microarrays, the hypothesis was accepted if p>10⁻³, and thedifferential ratio was set to 1.000 for those spots. All other spotshave a significant difference in expression between the tumor and normalsample. If the tumor sample has detectable expression and the normaldoes not, the ratio is truncated at 1000 since the value for expressionin the normal sample would be zero, and the ratio would not be amathematically useful value (e.g., infinity). If the normal sample hasdetectable expression and the tumor does not, the ratio is truncated to0.001, since the value for expression in the tumor sample would be zeroand the ratio would not be a mathematically useful value. These lattertwo situations are referred to herein as “on/off.” Database tables werepopulated using a 95% confidence level (p>0.05).

Tables 115-119 summarizes the results of the differential expressionanalysis, where the difference in the expression level in the colontumor cell relative to the matched normal colon cells is greater than orequal to 2 fold (“>=2×”), 2.5 fold (“>=2.5×”), or 5 fold (“>=5×”) in atleast 20% or more of the patients analyzed. Each table provides: the SEQID NO; the percentage of patients tested having a colon tumor thatexhibited at least 2 fold (“>=2×”), 2.5 fold (“>=2.5×”), or 5 fold(“>=5×”) increase in expression levels of the indicated gene relative tomatched normal colon tissue; and the ratio data for each patient sampletested (columns headed by “P#,” indicating the Patient IdentificationNumber, e.g., “P15” indicates the ration data for patient 15). TABLE 115% Pts SEQ ID % Pts >=2_5x % Pts NO >=2x T/N T/N >=5x T/N P15 P52 P121P125 13288 30.3 15.2 3.0 1.855 2.705 1.000 2.280 13292 45.5 39.4 18.22.196 1.719 0.604 2.388 13397 27.3 18.2 6.1 1.000 1.620 1.822 1.69213409 21.2 18.2 15.2 1000.000 0.001 2.345 1.000 13418 27.3 18.2 6.11.000 1.620 1.822 1.692 13425 45.5 12.1 3.0 1.870 3.104 1.361 2.38813516 42.4 9.1 0.0 2.211 2.347 1.000 1.493 13542 48.5 27.3 12.1 1.7353.110 1.379 2.277 13543 21.2 18.2 18.2 1.000 1.000 0.330 1.349 1354924.2 12.1 0.0 1.614 2.348 1.498 1.916 13568 21.2 18.2 18.2 1.000 1.0000.330 1.349 13599 21.2 9.1 6.1 1.000 1.000 2.211 1.182 13623 45.5 12.13.0 1.870 3.104 1.361 2.388 13624 48.5 30.3 3.0 1.000 1.592 2.248 2.31513651 27.3 18.2 6.1 1.000 1.620 1.822 1.692 13659 21.2 9.1 6.1 1.0001.000 2.211 1.182 13675 21.2 9.1 3.0 1.000 2.366 1.546 1.562 13676 21.29.1 3.0 1.000 2.366 1.546 1.562 13682 36.4 18.2 0.0 2.584 1.332 1.9521.641 13691 51.5 24.2 3.0 2.481 2.253 2.234 1.431 13735 21.2 18.2 15.21000.000 0.001 2.345 1.000 13804 21.2 9.1 3.0 1.000 2.366 1.546 1.56213808 42.4 15.2 0.0 1.489 2.019 3.022 1.121 13835 45.5 12.1 3.0 1.8703.104 1.361 2.388 13927 45.5 30.3 3.0 1.512 2.748 0.784 2.162 13940 24.26.1 0.0 1.190 1.000 0.656 1.456 14009 21.2 12.1 0.0 1.936 1.830 0.8311.347 14011 48.5 18.2 0.0 2.750 2.458 1.485 1.151 14014 48.5 21.2 0.02.069 3.002 1.229 1.631 14025 30.3 18.2 3.0 1.000 1.414 1.236 1.73814027 21.2 15.2 6.1 1.000 0.839 2.032 2.557 14080 30.3 18.2 3.0 1.0001.414 1.236 1.738 14081 30.3 18.2 3.0 1.000 1.414 1.236 1.738 14115 30.315.2 9.1 1.000 0.271 0.860 1.310 14131 24.2 21.2 15.2 1000.000 1000.0001.000 1.320 14185 30.3 15.2 3.0 1.855 2.705 1.000 2.280 14224 24.2 21.215.2 1000.000 1000.000 1.000 1.320 14225 39.4 21.2 3.0 1.612 2.281 0.7852.045 14261 39.4 21.2 3.0 1.612 2.281 0.785 2.045 14305 24.2 6.1 0.01.190 1.000 0.656 1.456 14319 21.2 12.1 0.0 1.936 1.830 0.831 1.34714320 39.4 21.2 3.0 1.612 2.281 0.785 2.045 14505 45.5 12.1 3.0 1.8703.104 1.361 2.388 14562 21.2 3.0 0.0 1.558 2.014 2.250 1.643 14583 24.26.1 0.0 1.190 1.000 0.656 1.456 14601 27.3 9.1 3.0 1.327 3.749 1.0002.045 14604 48.5 30.3 3.0 1.000 1.592 2.248 2.315 14688 30.3 15.2 3.01.855 2.705 1.000 2.280 14689 45.5 12.1 3.0 1.870 3.104 1.361 2.38814690 39.4 18.2 3.0 1.759 1.566 1.000 2.302 14747 39.4 18.2 3.0 1.7591.566 1.000 2.302 14824 33.3 15.2 0.0 1.829 1.622 1.882 1.957 14849 42.49.1 0.0 2.211 2.347 1.000 1.493 14870 45.5 12.1 3.0 1.870 3.104 1.3612.388 14909 48.5 27.3 12.1 1.735 3.110 1.379 2.277 14927 42.4 24.2 0.01.000 1.908 2.267 1.188 14949 33.3 15.2 0.0 1.829 1.622 1.882 1.95715014 42.4 15.2 3.0 2.059 2.753 1.679 1.587 15117 78.8 63.6 9.1 2.6254.493 1.642 2.743 15147 45.5 12.1 3.0 1.870 3.104 1.361 2.388 15150 66.748.5 6.1 1.000 4.075 1.754 2.436 15159 45.5 12.1 3.0 1.870 3.104 1.3612.388 15279 30.3 15.2 3.0 1.855 2.705 1.000 2.280 15293 30.3 18.2 0.01.285 2.400 0.767 1.270 15299 42.4 9.1 0.0 2.211 2.347 1.000 1.493 1534124.2 6.1 0.0 1.190 1.000 0.656 1.456 15347 24.2 6.1 0.0 1.190 1.0000.656 1.456 15373 27.3 21.2 0.0 3.505 0.793 0.809 1.348 15379 24.2 6.10.0 1.190 1.000 0.656 1.456 15408 33.3 21.2 9.1 1.000 0.296 3.016 0.79415413 60.6 48.5 12.1 6.263 1.000 1.832 1.937 15453 63.6 45.5 12.1 1.9452.010 0.547 3.325 15455 30.3 18.2 3.0 1.000 1.414 1.236 1.738 15460 24.26.1 0.0 1.190 1.000 0.656 1.456 15470 45.5 12.1 3.0 1.870 3.104 1.3612.388 15476 60.6 27.3 3.0 2.256 2.228 1.673 1.937 15490 33.3 24.2 3.02.591 0.483 2.580 1.440 15494 48.5 36.4 3.0 1.602 3.209 1.000 2.94215519 45.5 12.1 3.0 1.870 3.104 1.361 2.388 15525 24.2 3.0 0.0 1.9852.261 1.000 0.904 15535 54.5 42.4 6.1 1.886 1.000 1.503 3.375 15537 84.857.6 18.2 2.529 3.042 2.471 1.669 15551 54.5 36.4 3.0 2.008 0.686 3.1041.362 15564 30.3 15.2 3.0 1.855 2.705 1.000 2.280 15570 30.3 15.2 3.01.855 2.705 1.000 2.280 15577 42.4 9.1 0.0 2.211 2.347 1.000 1.493 1557942.4 21.2 9.1 2.497 1.837 3.249 1.497 15583 57.6 48.5 9.1 2.603 2.6421.000 1.939 15584 48.5 27.3 12.1 1.735 3.110 1.379 2.277 15586 42.4 9.10.0 2.211 2.347 1.000 1.493 15597 39.4 24.2 3.0 2.006 1.692 1.778 1.66215618 72.7 45.5 0.0 2.961 3.152 2.712 1.346

TABLE 116 SEQ ID NO P128 P130 P133 P141 P156 P228 P264 P266 13288 0.7131.800 1.955 0.663 0.466 1.457 2.262 1.236 13292 1.594 6.800 1.340 1.1311.000 2.647 1.628 1.190 13397 3.761 1.000 1.000 1.587 2.127 1.000 1.0001.000 13409 1000.000 1.000 1000.000 0.482 2.846 0.767 1.631 1.000 134183.761 1.000 1.000 1.587 2.127 1.000 1.000 1.000 13425 2.062 1.781 2.3021.000 1.000 1.306 2.099 1.357 13516 1.779 1.337 2.865 1.515 1.617 1.3012.098 1.733 13542 2.044 2.219 4.257 0.744 1.000 1.127 1.588 1.634 135431000.000 1000.000 1.000 1.000 0.566 1.554 1.000 1.000 13549 1.202 1.8522.370 1.000 1.000 1.114 1.399 1.239 13568 1000.000 1000.000 1.000 1.0000.566 1.554 1.000 1.000 13599 3.234 0.001 1.000 8.480 2.077 1.000 0.0011.445 13623 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 13624 1.6641.987 2.307 2.728 1.000 1.239 1.469 2.059 13651 3.761 1.000 1.000 1.5872.127 1.000 1.000 1.000 13659 3.234 0.001 1.000 8.480 2.077 1.000 0.0011.445 13675 1.531 1.553 1.854 2.044 1.363 1.786 1.877 1.644 13676 1.5311.553 1.854 2.044 1.363 1.786 1.877 1.644 13682 1.831 1.503 2.326 1.1301.773 1.379 2.318 2.019 13691 2.209 1.889 3.114 1.776 1.788 1.879 2.6662.257 13735 1000.000 1.000 1000.000 0.482 2.846 0.767 1.631 1.000 138041.531 1.553 1.854 2.044 1.363 1.786 1.877 1.644 13808 1.559 1.000 1.7403.133 2.186 1.869 2.023 2.483 13835 2.062 1.781 2.302 1.000 1.000 1.3062.099 1.357 13927 1.524 1.770 2.846 1.185 1.000 1.460 1.831 2.261 139401.182 1.636 1.418 1.298 1.000 1.000 1.127 0.774 14009 0.845 1.286 1.8721.000 1.000 1.295 1.722 1.785 14011 1.819 1.801 3.227 1.457 2.960 1.3882.086 2.410 14014 2.515 1.605 2.399 1.803 2.524 1.551 2.284 1.574 140251.000 0.754 2.234 3.723 1.000 1.285 1.771 2.246 14027 0.745 1.3321000.000 1.000 1.000 1.781 1.515 1.747 14080 1.000 0.754 2.234 3.7231.000 1.285 1.771 2.246 14081 1.000 0.754 2.234 3.723 1.000 1.285 1.7712.246 14115 2.331 1.641 1000.000 1.252 1.000 0.595 1.950 0.616 141312.888 1.000 0.001 1.000 1.694 0.001 1000.000 1.423 14185 0.713 1.8001.955 0.663 0.466 1.457 2.262 1.236 14224 2.888 1.000 0.001 1.000 1.6940.001 1000.000 1.423 14225 1.415 2.042 2.733 0.898 1.431 1.000 1.4592.009 14261 1.415 2.042 2.733 0.898 1.431 1.000 1.459 2.009 14305 1.1821.636 1.418 1.298 1.000 1.000 1.127 0.774 14319 0.845 1.286 1.872 1.0001.000 1.295 1.722 1.785 14320 1.415 2.042 2.733 0.898 1.431 1.000 1.4592.009 14505 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 14562 1.8041.641 1.876 1.335 0.766 1.245 1.500 1.000 14583 1.182 1.636 1.418 1.2981.000 1.000 1.127 0.774 14601 1.427 1.669 1.837 1.265 1.000 1.667 1.0001.374 14604 1.664 1.987 2.307 2.728 1.000 1.239 1.469 2.059 14688 0.7131.800 1.955 0.663 0.466 1.457 2.262 1.236 14689 2.062 1.781 2.302 1.0001.000 1.306 2.099 1.357 14690 1.518 1.997 2.298 2.273 1.000 1.234 1.1861.730 14747 1.518 1.997 2.298 2.273 1.000 1.234 1.186 1.730 14824 2.9591.821 2.234 1.181 1.827 1.000 2.042 1.970 14849 1.779 1.337 2.865 1.5151.617 1.301 2.098 1.733 14870 2.062 1.781 2.302 1.000 1.000 1.306 2.0991.357 14909 2.044 2.219 4.257 0.744 1.000 1.127 1.588 1.634 14927 2.1601.416 1.000 3.531 2.974 1.798 1.899 2.065 14949 2.959 1.821 2.234 1.1811.827 1.000 2.042 1.970 15014 1.479 1.669 2.442 1.352 1.367 1.605 2.1452.098 15117 1.839 2.548 2.954 2.234 1.816 1.352 3.390 2.541 15147 2.0621.781 2.302 1.000 1.000 1.306 2.099 1.357 15150 2.762 2.081 4.111 2.3062.391 1.675 2.572 3.031 15159 2.062 1.781 2.302 1.000 1.000 1.306 2.0991.357 15279 0.713 1.800 1.955 0.663 0.466 1.457 2.262 1.236 15293 1.8711.869 2.588 1.834 1.718 1.197 1.965 2.023 15299 1.779 1.337 2.865 1.5151.617 1.301 2.098 1.733 15341 1.182 1.636 1.418 1.298 1.000 1.000 1.1270.774 15347 1.182 1.636 1.418 1.298 1.000 1.000 1.127 0.774 15373 2.2970.855 1.659 1.607 0.252 1.602 2.866 1.292 15379 1.182 1.636 1.418 1.2981.000 1.000 1.127 0.774 15408 2.074 1.438 1.552 2.403 0.647 0.605 0.4690.528 15413 2.828 2.795 2.732 2.548 0.073 1.201 1.722 1.181 15453 1.7143.061 4.635 1.688 1.230 1.241 1.237 1.852 15455 1.000 0.754 2.234 3.7231.000 1.285 1.771 2.246 15460 1.182 1.636 1.418 1.298 1.000 1.000 1.1270.774 15470 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 15476 2.2292.131 2.194 2.235 2.121 1.388 3.468 2.115 15490 2.650 0.815 1.629 1.5860.155 1.408 2.830 1.636 15494 1.385 2.044 2.510 0.628 1.763 1.000 1.0001.687 15519 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 15525 1.4541.000 1.567 2.350 1.729 2.071 1.439 1.540 15535 2.843 2.931 1.690 1.6780.724 2.656 2.035 3.526 15537 2.490 1.937 3.729 2.105 2.224 2.547 2.6054.402 15551 3.412 2.374 1.404 4.761 3.241 2.253 1.384 1.912 15564 0.7131.800 1.955 0.663 0.466 1.457 2.262 1.236 15570 0.713 1.800 1.955 0.6630.466 1.457 2.262 1.236 15577 1.779 1.337 2.865 1.515 1.617 1.301 2.0981.733 15579 1.496 1.483 2.427 1.764 1.000 1.231 1.413 1.000 15583 1.4521.915 2.252 1.342 2.516 1.278 2.179 4.223 15584 2.044 2.219 4.257 0.7441.000 1.127 1.588 1.634 15586 1.779 1.337 2.865 1.515 1.617 1.301 2.0981.733 15597 1.778 1.200 2.169 1.462 1.570 1.784 1.937 2.633 15618 2.0641.288 2.075 2.527 2.239 1.745 3.772 3.393 15654 2.340 0.001 0.001 2.9274.830 1.708 1.651 1.586

TABLE 117 SEQ ID NO P268 P278 P295 P339 P341 P356 P360 P392 13288 1.0002.819 1.000 1.589 1.238 1.784 0.748 2.486 13292 1.194 1.000 1.000 1.4743.006 2.766 1.622 10.061 13397 2.953 2.030 8.118 1.000 2.854 1.0001000.000 0.001 13409 1000.000 1.332 1.000 0.344 1.537 1.000 0.001 0.46413418 2.953 2.030 8.118 1.000 2.854 1.000 1000.000 0.001 13425 1.1871.447 1.000 1.484 3.621 3.844 1.995 1.313 13516 1.422 2.018 2.385 1.2182.039 3.486 1.636 1.623 13542 1.268 1.563 1.870 2.056 6.240 6.491 2.2301.427 13543 1.000 1000.000 1.000 1.196 2.209 1000.000 0.001 1.000 135491.000 1.000 1.000 1.737 2.382 3.061 2.679 1.361 13568 1.000 1000.0001.000 1.196 2.209 1000.000 0.001 1.000 13599 2.467 2.166 21.707 0.6151.616 1.000 1.000 1.000 13623 1.187 1.447 1.000 1.484 3.621 3.844 1.9951.313 13624 2.359 1.552 2.918 1.647 4.706 3.623 1.979 1.677 13651 2.9532.030 8.118 1.000 2.854 1.000 1000.000 0.001 13659 2.467 2.166 21.7070.615 1.616 1.000 1.000 1.000 13675 1.221 1.796 1.995 1.780 1.726 2.9701.792 1.581 13676 1.221 1.796 1.995 1.780 1.726 2.970 1.792 1.581 136822.677 2.809 2.969 1.373 2.087 3.804 1.612 1.163 13691 2.468 5.262 4.0081.487 4.366 2.078 1.781 1.332 13735 1000.000 1.332 1.000 0.344 1.5371.000 0.001 0.464 13804 1.221 1.796 1.995 1.780 1.726 2.970 1.792 1.58113808 2.565 1.856 1.000 1.000 2.449 1.000 2.097 2.647 13835 1.187 1.4471.000 1.484 3.621 3.844 1.995 1.313 13927 1.369 1.000 1.000 1.679 3.0842.855 2.104 0.927 13940 1.677 2.420 2.263 1.314 1.473 2.523 1.776 2.24414009 1.412 1.431 3.103 1.000 2.847 2.621 1.000 1.117 14011 2.240 2.0401.000 1.000 2.450 3.440 2.045 1.998 14014 1.837 2.201 2.518 1.604 2.2482.989 1.570 1.409 14025 1.000 1.320 0.556 1.385 1.321 1.000 1.000 6.18514027 0.713 1000.000 0.632 2.389 0.202 1.000 1.000 0.356 14080 1.0001.320 0.556 1.385 1.321 1.000 1.000 6.185 14081 1.000 1.320 0.556 1.3851.321 1.000 1.000 6.185 14115 2.151 2.384 2.417 0.573 1.451 2.652 1.0000.734 14131 1.000 1.509 9.879 1000.000 2.327 0.001 1.236 0.870 141851.000 2.819 1.000 1.589 1.238 1.784 0.748 2.486 14224 1.000 1.509 9.8791000.000 2.327 0.001 1.236 0.870 14225 1.657 1.732 3.510 1.652 4.9464.071 2.194 1.932 14261 1.657 1.732 3.510 1.652 4.946 4.071 2.194 1.93214305 1.677 2.420 2.263 1.314 1.473 2.523 1.776 2.244 14319 1.412 1.4313.103 1.000 2.847 2.621 1.000 1.117 14320 1.657 1.732 3.510 1.652 4.9464.071 2.194 1.932 14505 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.31314562 0.718 1.000 1.000 1.675 2.301 1.361 2.161 1.825 14583 1.677 2.4202.263 1.314 1.473 2.523 1.776 2.244 14601 0.789 1.609 1.000 0.797 1.0002.075 2.491 2.505 14604 2.359 1.552 2.918 1.647 4.706 3.623 1.979 1.67714688 1.000 2.819 1.000 1.589 1.238 1.784 0.748 2.486 14689 1.187 1.4471.000 1.484 3.621 3.844 1.995 1.313 14690 1.864 1.428 2.631 1.854 3.4303.182 1.892 1.581 14747 1.864 1.428 2.631 1.854 3.430 3.182 1.892 1.58114824 2.495 2.090 3.320 1.000 3.907 2.976 1.875 1.000 14849 1.422 2.0182.385 1.218 2.039 3.486 1.636 1.623 14870 1.187 1.447 1.000 1.484 3.6213.844 1.995 1.313 14909 1.268 1.563 1.870 2.056 6.240 6.491 2.230 1.42714927 2.183 2.285 3.554 1.247 2.093 1.840 1.855 1.504 14949 2.495 2.0903.320 1.000 3.907 2.976 1.875 1.000 15014 2.006 1.696 2.261 1.611 2.1543.791 1.816 1.356 15117 1.535 2.851 4.154 2.055 6.047 4.103 3.367 2.02915147 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.313 15150 2.274 1.2664.526 2.591 5.409 3.138 2.675 1.391 15159 1.187 1.447 1.000 1.484 3.6213.844 1.995 1.313 15279 1.000 2.819 1.000 1.589 1.238 1.784 0.748 2.48615293 1.971 1.699 2.355 1.453 3.122 2.528 1.949 1.326 15299 1.422 2.0182.385 1.218 2.039 3.486 1.636 1.623 15341 1.677 2.420 2.263 1.314 1.4732.523 1.776 2.244 15347 1.677 2.420 2.263 1.314 1.473 2.523 1.776 2.24415373 2.516 0.852 1.775 0.818 4.294 2.281 1.119 0.890 15379 1.677 2.4202.263 1.314 1.473 2.523 1.776 2.244 15408 1.794 1.486 5.006 0.398 4.7680.001 2.344 2.434 15413 2.079 1.664 1.000 1.871 2.812 2.693 5.094 1.94715453 2.325 2.043 2.530 2.411 5.749 5.509 3.490 2.008 15455 1.000 1.3200.556 1.385 1.321 1.000 1.000 6.185 15460 1.677 2.420 2.263 1.314 1.4732.523 1.776 2.244 15470 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.31315476 1.977 1.676 1.774 1.542 2.538 1.867 2.312 1.000 15490 2.942 0.7291.772 0.861 15.794 2.349 1.363 0.808 15494 1.457 1.690 2.551 1.860 4.1143.548 3.125 0.792 15519 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.31315525 1.586 1.943 1.000 0.699 1.593 2.039 1.798 0.774 15535 2.157 1.9223.895 4.143 2.655 1.914 2.159 3.312 15537 3.442 3.933 5.994 1.448 8.6957.488 2.687 2.449 15551 2.467 1.000 7.584 1.417 3.693 1.947 1.539 4.42915564 1.000 2.819 1.000 1.589 1.238 1.784 0.748 2.486 15570 1.000 2.8191.000 1.589 1.238 1.784 0.748 2.486 15577 1.422 2.018 2.385 1.218 2.0393.486 1.636 1.623 15579 2.485 2.369 1.000 1.820 3.354 5.046 1.820 0.70315583 3.203 1.593 4.012 1.593 6.374 6.940 3.158 0.947 15584 1.268 1.5631.870 2.056 6.240 6.491 2.230 1.427 15586 1.422 2.018 2.385 1.218 2.0393.486 1.636 1.623 15597 2.439 1.482 2.156 1.390 3.500 3.654 1.655 0.77115618 2.448 2.617 4.003 1.289 2.940 3.894 2.277 1.202 15654 2.328 1.3599.253 0.383 1.835 0.001 1.000 0.714

TABLE 118 SEQ ID NO P393 P413 P505 P517 P534 P546 P577 P695 13288 1.0582.471 1.583 1.726 0.506 1.431 2.632 5.930 13292 14.260 2.516 1.498 3.7471.300 5.779 11.202 0.001 13397 1.000 0.001 1.000 1.000 0.001 1.000 3.3031.000 13409 1.000 1.000 0.458 1.249 0.001 1000.000 0.702 1.000 134181.000 0.001 1.000 1.000 0.001 1.000 3.303 1.000 13425 1.137 2.268 2.4141.382 2.107 2.210 2.384 5.256 13516 0.741 2.181 2.494 1.504 1.511 1.8312.064 4.421 13542 1.348 2.222 2.506 1.355 1.670 2.535 1.556 8.411 135431.000 1.000 1000.000 1.477 1.645 1.000 1.389 1.000 13549 0.914 1.6031.936 1.485 2.430 1.999 1.647 4.375 13568 1.000 1.000 1000.000 1.4771.645 1.000 1.389 1.000 13599 1.000 1.000 1.436 0.517 1.000 1.469 1.0001.000 13623 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 13624 1.2243.432 2.806 1.328 2.470 2.592 1.929 6.973 13651 1.000 0.001 1.000 1.0000.001 1.000 3.303 1.000 13659 1.000 1.000 1.436 0.517 1.000 1.469 1.0001.000 13675 1.241 1.841 1.470 1.000 1.672 2.218 1.649 7.555 13676 1.2411.841 1.470 1.000 1.672 2.218 1.649 7.555 13682 1.258 2.153 1.849 1.4451.000 1.531 1.637 3.302 13691 1.000 1.327 2.871 1.116 1.903 2.200 2.6440.001 13735 1.000 1.000 0.458 1.249 0.001 1000.000 0.702 1.000 138041.241 1.841 1.470 1.000 1.672 2.218 1.649 7.555 13808 1.560 1.982 2.1591.278 1.425 1.204 3.046 2.068 13835 1.137 2.268 2.414 1.382 2.107 2.2102.384 5.256 13927 0.763 1.602 2.797 1.265 2.765 2.236 2.548 5.071 139401.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 14009 2.102 1.689 4.4290.830 1.000 1.000 2.108 2.208 14011 1.935 1.911 2.812 1.000 1.854 1.7932.441 0.001 14014 1.320 1.404 1.553 1.000 1.957 1.816 2.156 3.745 140251.219 2.547 1.288 2.539 3.936 3.625 2.363 1.955 14027 0.851 0.750 0.8150.258 0.712 1.229 0.190 1.000 14080 1.219 2.547 1.288 2.539 3.936 3.6252.363 1.955 14081 1.219 2.547 1.288 2.539 3.936 3.625 2.363 1.955 141152.765 1.000 2.202 0.472 0.490 1.417 0.725 0.001 14131 1.000 1.000 1.0001.000 1.000 1.530 0.769 1.000 14185 1.058 2.471 1.583 1.726 0.506 1.4312.632 5.930 14224 1.000 1.000 1.000 1.000 1.000 1.530 0.769 1.000 142251.322 2.608 1.910 1.199 1.635 1.893 1.473 5.842 14261 1.322 2.608 1.9101.199 1.635 1.893 1.473 5.842 14305 1.710 2.337 1.898 0.892 1.347 1.9081.136 3.404 14319 2.102 1.689 4.429 0.830 1.000 1.000 2.108 2.208 143201.322 2.608 1.910 1.199 1.635 1.893 1.473 5.842 14505 1.137 2.268 2.4141.382 2.107 2.210 2.384 5.256 14562 1.000 1.518 1.980 1.518 2.526 1.5881.865 2.251 14583 1.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 146010.743 2.126 1.613 1.177 2.128 1.000 1.951 6.931 14604 1.224 3.432 2.8061.328 2.470 2.592 1.929 6.973 14688 1.058 2.471 1.583 1.726 0.506 1.4312.632 5.930 14689 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 146901.205 3.301 2.749 1.256 2.474 2.345 1.826 8.108 14747 1.205 3.301 2.7491.256 2.474 2.345 1.826 8.108 14824 1.000 1.793 2.719 1.679 1.000 1.5492.076 0.001 14849 0.741 2.181 2.494 1.504 1.511 1.831 2.064 4.421 148701.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 14909 1.348 2.222 2.5061.355 1.670 2.535 1.556 8.411 14927 2.809 1.534 1.366 1.197 2.545 1.9641.506 0.001 14949 1.000 1.793 2.719 1.679 1.000 1.549 2.076 0.001 150141.249 2.009 1.832 1.488 1.379 1.975 2.128 13.930 15117 1.781 2.929 2.1832.759 3.853 3.092 2.051 7.549 15147 1.137 2.268 2.414 1.382 2.107 2.2102.384 5.256 15150 1.000 3.187 2.564 0.756 1.226 3.841 3.201 16.724 151591.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 15279 1.058 2.471 1.5831.726 0.506 1.431 2.632 5.930 15293 1.952 1.472 1.917 1.516 2.305 2.6772.620 2.660 15299 0.741 2.181 2.494 1.504 1.511 1.831 2.064 4.421 153411.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 15347 1.710 2.337 1.8980.892 1.347 1.908 1.136 3.404 15373 0.537 1.790 0.727 0.750 0.329 1.1001.239 0.001 15379 1.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 154080.852 1.789 3.765 0.686 3.176 1.591 1.852 0.001 15413 2.044 17.760 4.0341.988 0.026 3.908 2.394 42.662 15453 1.088 5.833 3.519 1.572 2.641 4.0111.695 7.783 15455 1.219 2.547 1.288 2.539 3.936 3.625 2.363 1.955 154601.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 15470 1.137 2.268 2.4141.382 2.107 2.210 2.384 5.256 15476 1.000 3.033 1.912 1.699 2.147 2.7802.155 2.518 15490 0.337 2.339 0.768 0.563 0.359 1.242 1.492 1.000 154941.000 2.266 2.040 1.000 2.747 2.620 1.718 14.145 15519 1.137 2.268 2.4141.382 2.107 2.210 2.384 5.256 15525 1.243 1.766 1.547 0.843 1.000 1.4982.122 4.421 15535 5.268 1.518 2.253 3.678 0.766 1.565 1.000 1.853 155370.815 2.497 3.234 2.275 2.344 3.596 5.023 12.124 15551 1.128 0.885 1.2371.434 3.327 3.206 1.355 0.001 15564 1.058 2.471 1.583 1.726 0.506 1.4312.632 5.930 15570 1.058 2.471 1.583 1.726 0.506 1.431 2.632 5.930 155770.741 2.181 2.494 1.504 1.511 1.831 2.064 4.421 15579 1.240 2.239 2.8411.000 2.270 2.614 0.583 5.244 15583 0.633 2.821 2.976 1.253 1.675 3.6572.284 8.587 15584 1.348 2.222 2.506 1.355 1.670 2.535 1.556 8.411 155860.741 2.181 2.494 1.504 1.511 1.831 2.064 4.421 15597 1.000 1.801 1.9781.000 3.188 1.607 2.276 13.068 15618 0.790 3.524 3.377 2.062 2.123 1.9591.626 1.000 15654 0.001 1.346 1.831 1.000 1.646 1.944 1.549 1.000

TABLE 119 SEQ ID NO P784 P786 P791 P888 P889 13288 1.000 1.000 4.2021.464 2.147 13292 1.000 1.276 14.034 4.139 3.640 13397 1.708 2.247 1.0000.441 0.001 13409 1.391 1.857 1.000 0.402 1.000 13418 1.708 2.247 1.0000.441 0.001 13425 1.328 1.421 2.456 1.910 2.069 13516 1.243 1.679 2.2282.333 1.774 13542 0.819 1.632 2.808 5.465 2.307 13543 1000.000 0.7581.000 1.000 1.000 13549 1.000 1.000 1.834 2.776 1.636 13568 1000.0000.758 1.000 1.000 1.000 13599 1.000 1.000 1.000 0.642 1.000 13623 1.3281.421 2.456 1.910 2.069 13624 1.000 1.416 2.862 2.690 1.645 13651 1.7082.247 1.000 0.441 0.001 13659 1.000 1.000 1.000 0.642 1.000 13675 1.0001.821 1.628 2.276 2.501 13676 1.000 1.821 1.628 2.276 2.501 13682 1.0001.888 1.915 2.276 1.481 13691 3.336 1.677 2.208 1.000 1.976 13735 1.3911.857 1.000 0.402 1.000 13804 1.000 1.821 1.628 2.276 2.501 13808 1.0001.629 2.152 1.000 1.792 13835 1.328 1.421 2.456 1.910 2.069 13927 1.0001.997 2.083 3.178 3.444 13940 1.000 1.780 1.000 2.177 2.258 14009 1.3560.696 1.000 1.000 1.463 14011 2.324 1.000 2.379 1.407 2.833 14014 2.1371.934 2.482 2.035 3.980 14025 0.796 1.000 1.737 1.000 2.218 14027 2.5313.138 0.395 1.000 1.000 14080 0.796 1.000 1.737 1.000 2.218 14081 0.7961.000 1.737 1.000 2.218 14115 1000.000 1.984 1000.000 1.374 1.000 141313.031 1.000 1.000 1.000 1.000 14185 1.000 1.000 4.202 1.464 2.147 142243.031 1.000 1.000 1.000 1.000 14225 0.876 1.781 2.424 4.143 1.977 142610.876 1.781 2.424 4.143 1.977 14305 1.000 1.780 1.000 2.177 2.258 143191.356 0.696 1.000 1.000 1.463 14320 0.876 1.781 2.424 4.143 1.977 145051.328 1.421 2.456 1.910 2.069 14562 1.000 1.000 1.992 2.144 1.615 145831.000 1.780 1.000 2.177 2.258 14601 1.290 1.000 1.000 1.995 2.203 146041.000 1.416 2.862 2.690 1.645 14688 1.000 1.000 4.202 1.464 2.147 146891.328 1.421 2.456 1.910 2.069 14690 0.816 1.000 2.196 2.446 1.518 147470.816 1.000 2.196 2.446 1.518 14824 1.585 1.889 2.178 1.806 1.867 148491.243 1.679 2.228 2.333 1.774 14870 1.328 1.421 2.456 1.910 2.069 149090.819 1.632 2.808 5.465 2.307 14927 2.810 2.638 1.976 1.491 2.955 149491.585 1.889 2.178 1.806 1.867 15014 1.253 1.994 1.874 3.193 2.663 151171.559 2.762 5.043 4.135 3.753 15147 1.328 1.421 2.456 1.910 2.069 151501.306 1.940 2.293 3.897 1.624 15159 1.328 1.421 2.456 1.910 2.069 152791.000 1.000 4.202 1.464 2.147 15293 1.511 1.357 1.632 1.891 1.895 152991.243 1.679 2.228 2.333 1.774 15341 1.000 1.780 1.000 2.177 2.258 153471.000 1.780 1.000 2.177 2.258 15373 0.573 2.678 1.000 2.507 3.278 153791.000 1.780 1.000 2.177 2.258 15408 7.866 1.000 1000.000 1.719 1.00015413 2.625 2.744 4.155 2.105 4.438 15453 1.000 2.139 3.014 3.159 3.38115455 0.796 1.000 1.737 1.000 2.218 15460 1.000 1.780 1.000 2.177 2.25815470 1.328 1.421 2.456 1.910 2.069 15476 1.489 2.750 2.910 5.049 4.00615490 0.419 3.014 0.575 2.397 3.558 15494 1.000 1.815 2.513 3.487 2.18015519 1.328 1.421 2.456 1.910 2.069 15525 1.000 1.493 2.186 1.000 2.22215535 1.267 3.638 1.623 5.889 3.339 15537 1.746 2.363 5.515 2.674 3.63715551 2.399 3.587 3.625 2.567 2.417 15564 1.000 1.000 4.202 1.464 2.14715570 1.000 1.000 4.202 1.464 2.147 15577 1.243 1.679 2.228 2.333 1.77415579 0.397 1.000 1.472 5.315 2.250 15583 1.000 1.939 2.505 4.525 2.67415584 0.819 1.632 2.808 5.465 2.307 15586 1.243 1.679 2.228 2.333 1.77415597 1.295 1.658 2.836 2.766 2.873 15618 2.167 2.157 3.410 2.828 3.79415654 1.352 1.000 2.727 0.583 1.000

In general, a polynucleotide is said to represent a significantlydifferentially expressed gene between two samples when there isdetectable levels of expression in at least one sample and the ratiovalue is greater than at least about 1.2 fold, preferably greater thanat least about 1.5 fold, more preferably greater than at least about 2fold, where the ratio value is calculated using the method describedabove.

A differential expression ratio of 1 indicates that the expression levelof the gene in the tumor cell was not statistically different fromexpression of that gene in normal colon cells of the same patient. Adifferential expression ratio significantly greater than 1 in cancerouscolon cells relative to normal colon cells indicates that the gene isincreased in expression in cancerous cells relative to normal cells,indicating that the gene plays a role in the development of thecancerous phenotype, and may be involved in promoting metastasis of thecell. Detection of gene products from such genes can provide anindicator that the cell is cancerous, and may provide a therapeuticand/or diagnostic target.

Likewise, a differential expression ratio significantly less than 1 incancerous colon cells relative to normal colon cells indicates that, forexample, the gene is involved in suppression of the cancerous phenotype.Increasing activity of the gene product encoded by such a gene, orreplacing such activity, can provide the basis for chemotherapy. Suchgene can also serve as markers of cancerous cells, e.g., the absence ordecreased presence of the gene product in a colon cell relative to anormal colon cell indicates that the cell may be cancerous.

Example 76 Functional Analysis of Gene Products Differentially Expressedin Cancer in Patients

The gene products of genes differentially expressed in cancerous cellsare further analyzed to confirm the role and function of the geneproduct in tumorgenesis, e.g., in promoting or inhibiting development ofa metastatic phenotype.

Blocking Expression of Gene Products Using Antisense

The effect of single genes upon development of cancer is assessedthrough use of antisense oligonucleotides specific for sequencescorresponding to a selected sequence. Antisense oligonucleotides areprepared based upon a selected sequence that corresponds to a gene ofinterest. The antisense oligonucleotide is introduced into a test celland the effect upon expression of the corresponding gene, as well as theeffect upon a phenotype of interest assessed (e.g., a normal cell isexamined for induction of the cancerous phenotype, or a cancerous cellis examined for suppression of a cancerous phenotype (e.g., suppressionof metastasis)).

Blocking Function of Gene Products Using Gene Product-SpecificAntibodies and/or Small Molecule Inhibitors

The function of gene products corresponding to genes/clusters identifiedherein can be assessed by blocking function of the gene products in thecell. For example, where the gene product is secreted, blockingantibodies can generated and added to cells to examine the effect uponthe cell phenotype in the context of, for example, the transformation ofthe cell to a cancerous, particularly a metastatic, phenotype. In orderto generate antibodies, a clone corresponding to a selected geneproduct/cluster is selected, and a sequence that represents a partial orcomplete coding sequence is obtained. The resulting clone is thenexpressed, the polypeptide produced isolated, and antibodies generated.The antibodies are then combined with cells and the effect upontumorigenesis assessed.

Where the gene product of the gene/clusters identified herein exhibitssequence homology to a protein of known function (e.g., to a specifickinase or protease) and/or to a protein family of known function (e.g.,contains a domain or other consensus sequence present in a proteasefamily or in a kinase family), then the role of the gene product intumorigenesis, as well as the activity of the gene product, can beexamined using small molecule that inhibit or enhance function of thecorresponding protein or protein family.

Those skilled in the art will recognize, or be able to ascertain, usingnot more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such specific embodimentsand equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Deposit Information. The following materials were deposited with theAmerican Type Culture Collection (CMCC=Chiron Master CultureCollection). TABLE 111 Cell Lines Deposited with ATCC ATCC CMCC CellLine Deposit Date Accession No. Accession No. KM12L4 Mar. 19, 1998CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15,1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containingspecific clones, were assigned an “ES” number (internal reference) anddeposited with the ATCC. Table 112 (inserted before the claims) providesthe ATCC Accession Nos. and internal references (CMCC Nos.) of the ESdeposits, all of which were deposited on or before the filing date ofthe present application. The names of the clones contained within eachof these deposits are provided in Table 113 (inserted before theclaims). TABLE 112 ES # CMCC# ATCC Deposit# 85 5175 PTA-1313 86 5176PTA-1314 87 5177 PTA-1315 88 5178 PTA-1316 89 5179 PTA-1317 90 5180PTA-1318 91 5181 PTA-1319 92 5182 PTA-1320 93 5183 PTA-1321 94 5184PTA-1322 95 5185 PTA-1323 96 5186 PTA-1324 97 5187 PTA-1325 98 5188PTA-1326 99 5189 PTA-1327 100 5190 PTA-1328 101 5191 PTA-1329 102 5192PTA-1330 103 5193 PTA-1331 104 5194 PTA-1332 105 5195 PTA-1333 106 5196PTA-1334 107 5197 PTA-1335 108 5198 PTA-1336 109 5199 PTA-1372 110 5200PTA-1373 111 5201 PTA-1374 112 5202 PTA-1375 113 5203 PTA-1376 114 5204PTA-1377 115 5205 PTA-1378 116 5206 PTA-1379 117 5207 PTA-1380 118 5208PTA-1381 122 5212 PTA-1382 123 5213 PTA-1383 124 5214 PTA-1384 125 5215PTA-1385 126 5216 PTA-1386 127 5217 PTA-1387 128 5218 PTA-1388 129 5219PTA-1389 130 5220 PTA-1390 131 5221 PTA-1391 132 5222 PTA-1392 133 5223PTA-1393 134 5209 PTA-1431 135 5210 PTA-1432 136 5238 PTA-1497

TABLE 113 ES No. Clone Name ES 85 M00057077B:D02 ES 85 M00057078D:C12 ES85 M00057079D:E09 ES 85 M00057080C:C02 ES 85 M00057085A:A03 ES 85M00057088B:C02 ES 85 M00057091A:C03 ES 85 M00057091A:C04 ES 85M00057091C:E12 ES 85 M00057093B:F09 ES 85 M00057099C:C08 ES 85M00057100C:E09 ES 85 M00057100D:B03 ES 85 M00057103A:E11 ES 85M00057103A:H09 ES 85 M00057104B:F08 ES 85 M00057106B:A03 ES 85M00057106C:E02 ES 85 M00057106D:B06 ES 85 M00057108B:F04 ES 85M00057108D:E09 ES 85 M00057108D:E09 ES 85 M00057112D:B09 ES 85M00057114D:B10 ES 85 M00057117D:G11 ES 85 M00057118C:C02 ES 85M00057120D:E12 ES 85 M00057124B:D10 ES 85 M00057127A:F11 ES 85M00057127B:G07 ES 85 M00057130C:H11 ES 85 M00057131C:B01 ES 85M00057132C:F08 ES 85 M00057133D:F01 ES 85 M00057134A:C01 ES 85M00057134C:A01 ES 85 M00057134D:G10 ES 85 M00057135D:H04 ES 85M00057136A:F01 ES 85 M00057141B:B02 ES 85 M00057141D:D02 ES 85M00057142A:A07 ES 85 M00057143C:E05 ES 85 M00057145A:D05 ES 85M00057146D:C09 ES 85 M00057147A:A01 ES 85 M00057150A:C10 ES 85M00057151A:B04 ES 86 M00057154A:D06 ES 86 M00057154C:B04 ES 86M00057161B:E09 ES 86 M00057162A:C07 ES 86 M00057162B:H02 ES 86M00057162D:D10 ES 86 M00057163D:B01 ES 86 M00057165D:E12 ES 86M00057167B:E12 ES 86 M00057167B:G12 ES 86 M00057167D:B07 ES 86M00057170C:H03 ES 86 M00057174B:C06 ES 86 M00057174B:G12 ES 86M00057174C:H12 ES 86 M00057180A:H11 ES 86 M00057181C:D06 ES 86M00057182D:B11 ES 86 M00057189B:G05 ES 86 M00057191A:A03 ES 86M00057192B:E02 ES 86 M00057192D:G02 ES 86 M00057196A:E03 ES 86M00057196C:F04 ES 86 M00057203C:E06 ES 86 M00057208A:A02 ES 86M00057208C:C06 ES 86 M00057208C:D08 ES 86 M00057211B:F07 ES 86M00057211D:A06 ES 86 M00057215B:B02 ES 86 M00057217B:B07 ES 86M00057218D:C01 ES 86 M00057223C:C06 ES 86 M00057224B:C10 ES 86M00057226D:C05 ES 86 M00057229D:F06 ES 86 M00057230C:D12 ES 86M00057231C:G09 ES 86 M00057231D:A09 ES 86 M00057232B:D06 ES 86M00057233A:F07 ES 86 M00057233B:E04 ES 86 M00057236B:H06 ES 86M00057237A:B11 ES 86 M00057239A:G08 ES 86 M00057241B:B04 ES 86M00057242B:F07 ES 87 M00057242D:B09 ES 87 M00057242D:H05 ES 87M00057249A:C06 ES 87 M00057259A:H10 ES 87 M00057259B:B08 ES 87M00057266C:D04 ES 87 M00057266C:G12 ES 87 M00057268C:E10 ES 87M00057270B:H09 ES 87 M00057270C:E04 ES 87 M00057271C:E01 ES 87M00057272A:B03 ES 87 M00057272C:H04 ES 87 M00057272D:A01 ES 87M00057275B:A12 ES 87 M00057277B:C09 ES 87 M00057277B:E10 ES 87M00057279A:G02 ES 87 M00057280C:A06 ES 87 M00057283A:E06 ES 87M00057288D:E08 ES 87 M00057291C:B06 ES 87 M00057297A:F03 ES 87M00057300B:F02 ES 87 M00057301B:H12 ES 87 M00057304A:E01 ES 87M00057306B:H07 ES 87 M00057312B:E11 ES 87 M00057318B:B09 ES 87M00057318C:A03 ES 87 M00057324A:D12 ES 87 M00057325C:C10 ES 87M00057333A:F09 ES 87 M00057334B:F01 ES 87 M00057337B:G02 ES 87M00057340B:C12 ES 87 M00042355A:G02 ES 87 M00042355D:C01 ES 87M00042442D:A02 ES 87 M00042444D:G05 ES 87 M00042444D:H08 ES 87M00042450D:H10 ES 87 M00042453C:E01 ES 87 M00042460D:A07 ES 87M00042517C:F07 ES 87 M00042518D:A06 ES 87 M00042520A:F04 ES 88M00042520A:F09 ES 88 M00042520A:F09 ES 88 M00043296C:B10 ES 88M00043300A:H11 ES 88 M00043301A:F06 ES 88 M00043301D:H09 ES 88M00043304A:D01 ES 88 M00043304B:C05 ES 88 M00043304B:C05 ES 88M00043306D:B07 ES 88 M00043309B:H07 ES 88 M00043310C:B03 ES 88M00043313A:A03 ES 88 M00043313A:G07 ES 88 M00043313D:C06 ES 88M00043314C:H04 ES 88 M00043317A:H01 ES 88 M00043317C:F04 ES 88M00043323C:D04 ES 88 M00043324D:D04 ES 88 M00043327D:H02 ES 88M00043327D:H02 ES 88 M00043336B:E08 ES 88 M00043338A:B03 ES 88M00043338B:A03 ES 88 M00043345B:C03 ES 88 M00043347B:G12 ES 88M00043349A:C08 ES 88 M00043350B:H06 ES 88 M00043350C:H09 ES 88M00043352A:E09 ES 88 M00043352D:B05 ES 88 M00043354D:C01 ES 88M00043355D:H11 ES 88 M00043361D:D05 ES 88 M00043365A:C06 ES 88M00043374A:B02 ES 88 M00043374B:B06 ES 88 M00043377A:C03 ES 88M00043379D:C07 ES 88 M00043381B:E10 ES 88 M00043386D:A06 ES 88M00043388D:C09 ES 88 M00043394D:B06 ES 88 M00043397B:B02 ES 88M00043397C:B09 ES 88 M00043503C:C08 ES 88 M00043503C:E05 ES 89M00043504C:G06 ES 89 M00043504D:G08 ES 89 M00043506A:H09 ES 89M00043507A:D05 ES 89 M00043508A:A08 ES 89 M00043508D:C01 ES 89M00054486A:B11 ES 89 M00054493A:A10 ES 89 M00054494A:E01 ES 89M00054496A:B09 ES 89 M00054499B:E11 ES 89 M00054499B:E11 ES 89M00054502A:D01 ES 89 M00054502C:E02 ES 89 M00054507A:C11 ES 89M00054510D:H09 ES 89 M00054513A:A12 ES 89 M00054518D:D03 ES 89M00054520C:B05 ES 89 M00054521D:F04 ES 89 M00054522B:H11 ES 89M00054523D:A10 ES 89 M00054524D:B02 ES 89 M00054534D:D02 ES 89M00054535C:H09 ES 89 M00054542C:A08 ES 89 M00054551C:G03 ES 89M00054555C:G12 ES 89 M00054561D:E06 ES 89 M00054563B:C09 ES 89M00054568A:G11 ES 89 M00054569A:H07 ES 89 M00054571C:C01 ES 89M00054572B:C01 ES 89 M00054575C:C01 ES 89 M00054580C:D11 ES 89M00054583A:F05 ES 89 M00054587A:F09 ES 89 M00054590C:G02 ES 89M00054591C:H07 ES 89 M00054595A:B02 ES 89 M00054595B:H09 ES 89M00054596B:B07 ES 89 M00054600D:G07 ES 89 M00054601A:H10 ES 89M00054601D:E08 ES 89 M00054602A:C04 ES 90 M00054602B:D02 ES 90M00054604A:D09 ES 90 M00054604A:D09 ES 90 M00054605C:D01 ES 90M00054609A:F01 ES 90 M00054609D:H06 ES 90 M00054611C:F02 ES 90M00054613A:D09 ES 90 M00054613A:D09 ES 90 M00054617B:A09 ES 90M00054621B:C06 ES 90 M00054621D:D11 ES 90 M00054629C:E09 ES 90M00054636B:B03 ES 90 M00054636C:A02 ES 90 M00054636C:F02 ES 90M00054638A:D09 ES 90 M00054638B:C08 ES 90 M00054646C:B01 ES 90M00054647D:H02 ES 90 M00054648C:H10 ES 90 M00054660D:F05 ES 90M00054665B:H08 ES 90 M00054665D:E11 ES 90 M00054677C:D02 ES 90M00054678A:E07 ES 90 M00054679B:D12 ES 90 M00054680B:E06 ES 90M00054680D:B11 ES 90 M00054681C:B02 ES 90 M00054684C:H12 ES 90M00054689D:E12 ES 90 M00054691A:E05 ES 90 M00054692B:D01 ES 90M00054694D:G04 ES 90 M00054706B:C09 ES 90 M00054707B:B08 ES 90M00054707B:E05 ES 90 M00054713A:D12 ES 90 M00054720D:D12 ES 90M00054720D:F11 ES 90 M00054721C:F11 ES 90 M00054722C:D01 ES 90M00054722D:C08 ES 90 M00054726A:F08 ES 90 M00054727D:E10 ES 90M00054727D:H06 ES 90 M00054728B:E08 ES 91 M00054728D:B10 ES 91M00054729A:E01 ES 91 M00054731C:C12 ES 91 M00054732D:E03 ES 91M00054734D:H10 ES 91 M00054739A:G03 ES 91 M00054739C:D03 ES 91M00054739C:E06 ES 91 M00054740A:H08 ES 91 M00054741A:C10 ES 91M00054741A:E10 ES 91 M00054741D:G10 ES 91 M00054743C:E02 ES 91M00054745D:A03 ES 91 M00054747A:F01 ES 91 M00054747D:C06 ES 91M00054750C:D12 ES 91 M00054752B:A07 ES 91 M00054755B:H06 ES 91M00054759A:B08 ES 91 M00054760A:A12 ES 91 M00054762B:F07 ES 91M00054765B:C05 ES 91 M00054766C:B04 ES 91 M00054769A:F07 ES 91M00054772C:C06 ES 91 M00054773A:A12 ES 91 M00054776B:F01 ES 91M00054779A:F07 ES 91 M00054780C:G08 ES 91 M00054781B:B04 ES 91M00054802A:G02 ES 91 M00054804D:H12 ES 91 M00054808A:D07 ES 91M00054808B:F08 ES 91 M00054810B:H02 ES 91 M00054812B:A05 ES 91M00054812D:C07 ES 91 M00054812D:C07 ES 91 M00054815C:E01 ES 91M00054816C:D11 ES 91 M00054821A:C11 ES 91 M00054823D:H07 ES 91M00054826B:C10 ES 91 M00054826B:E05 ES 91 M00054826D:C10 ES 91M00054827B:H01 ES 92 M00054832D:E09 ES 92 M00054836A:B05 ES 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125M00056434D:E07 ES 126 M00056480B:C12 ES 126 M00056480D:A10 ES 126M00056481A:F02 ES 126 M00056483D:F06 ES 126 M00056484B:G02 ES 126M00056485B:B12 ES 126 M00056490D:E02 ES 126 M00056491D:G08 ES 126M00056496B:A01 ES 126 M00056496C:H09 ES 126 M00056499C:F05 ES 126M00056501C:H07 ES 126 M00056503B:G11 ES 126 M00056503B:G11 ES 126M00056505B:H02 ES 126 M00056505D:D07 ES 126 M00056506C:G12 ES 126M00056507D:B10 ES 126 M00056508B:B10 ES 126 M00056511A:H12 ES 126M00056512B:C06 ES 126 M00056512C:E09 ES 126 M00056512D:C12 ES 126M00056514B:E08 ES 126 M00056514C:G01 ES 126 M00056515C:C05 ES 126M00056517B:G03 ES 126 M00056519C:H01 ES 126 M00056526C:E11 ES 126M00056529D:F12 ES 126 M00056529D:H09 ES 126 M00056530A:D01 ES 126M00056532B:G06 ES 126 M00056534A:D11 ES 126 M00056537B:H05 ES 126M00056537C:A09 ES 126 M00056541B:A08 ES 126 M00056547A:C04 ES 126M00056548A:C11 ES 126 M00056551A:F02 ES 126 M00056552A:A10 ES 126M00056552D:B10 ES 126 M00056555A:F09 ES 126 M00056556C:G01 ES 126M00056557C:D02 ES 126 M00056561C:D08 ES 126 M00056564C:E09 ES 126M00056566C:H01 ES 127 M00056574B:A07 ES 127 M00056580B:F10 ES 127M00056591C:E03 ES 127 M00056592A:F04 ES 127 M00056592C:C03 ES 127M00056592D:D07 ES 127 M00056592D:D07 ES 127 M00056593B:E05 ES 127M00056594C:C06 ES 127 M00056594C:C10 ES 127 M00056595A:A02 ES 127M00056595A:C07 ES 127 M00056595B:F02 ES 127 M00056596A:E02 ES 127M00056596C:E06 ES 127 M00056596C:H08 ES 127 M00056597A:F07 ES 127M00056597D:C02 ES 127 M00056599D:D11 ES 127 M00056600D:H07 ES 127M00056603C:D01 ES 127 M00056608C:E04 ES 127 M00056610B:H12 ES 127M00056613A:A05 ES 127 M00056616B:C08 ES 127 M00056616D:A10 ES 127M00056617B:H06 ES 127 M00056618A:B02 ES 127 M00056618B:F06 ES 127M00056618D:F11 ES 127 M00056620D:E12 ES 127 M00056622D:C03 ES 127M00056624D:H05 ES 127 M00056628C:F01 ES 127 M00056631B:G05 ES 127M00056631D:C08 ES 127 M00056631D:D03 ES 127 M00056633B:B07 ES 127M00056635A:A11 ES 127 M00056635A:E09 ES 127 M00056638A:D08 ES 127M00056638B:B01 ES 127 M00056639A:E02 ES 127 M00056643D:G06 ES 127M00056645C:B11 ES 127 M00056645D:F06 ES 127 M00056646C:C02 ES 127M00056646D:G05 ES 128 M00056652D:F04 ES 128 M00056656C:H03 ES 128M00056659C:G08 ES 128 M00056661B:A09 ES 128 M00056661D:E05 ES 128M00056662B:F03 ES 128 M00056664B:G06 ES 128 M00056664C:B07 ES 128M00056665B:A11 ES 128 M00056665C:E05 ES 128 M00056666A:C08 ES 128M00056669B:G07 ES 128 M00056670A:A11 ES 128 M00056673D:E06 ES 128M00056674B:E05 ES 128 M00056674D:H04 ES 128 M00056682D:F10 ES 128M00056683C:B09 ES 128 M00056684D:A05 ES 128 M00056684D:F11 ES 128M00056688B:F05 ES 128 M00056690C:F09 ES 128 M00056693C:C08 ES 128M00056695A:H09 ES 128 M00056697C:E03 ES 128 M00056698C:E12 ES 128M00056701B:E08 ES 128 M00056703A:D06 ES 128 M00056705D:E07 ES 128M00056707B:E02 ES 128 M00056707D:D05 ES 128 M00056708C:C06 ES 128M00056708D:D11 ES 128 M00056709A:A05 ES 128 M00056710A:C01 ES 128M00056710B:F05 ES 128 M00056710B:H09 ES 128 M00056710D:F07 ES 128M00056711A:C01 ES 128 M00056711A:F05 ES 128 M00056711A:F05 ES 128M00056711D:A05 ES 128 M00056712C:A07 ES 128 M00056712C:B06 ES 128M00056713D:G08 ES 128 M00056714C:H06 ES 128 M00056715A:D10 ES 128M00056715A:E04 ES 129 M00056715A:G01 ES 129 M00056715B:C01 ES 129M00056715D:C04 ES 129 M00056715D:E08 ES 129 M00056717B:C04 ES 129M00056718C:B01 ES 129 M00056718C:G02 ES 129 M00056719A:D06 ES 129M00056719A:F12 ES 129 M00056719B:A09 ES 129 M00056721A:F07 ES 129M00056722A:G01 ES 129 M00056723B:D10 ES 129 M00056723C:C11 ES 129M00056724D:E11 ES 129 M00056726C:G05 ES 129 M00056728A:H05 ES 129M00056728B:D05 ES 129 M00056729B:D04 ES 129 M00056729C:H12 ES 129M00056733C:D09 ES 129 M00056735D:B08 ES 129 M00056737B:G07 ES 129M00056739A:D11 ES 129 M00056739B:D08 ES 129 M00056740C:B05 ES 129M00056741B:C06 ES 129 M00056746D:A02 ES 129 M00056746D:D06 ES 129M00056747A:D05 ES 129 M00056752A:E01 ES 129 M00056753D:A10 ES 129M00056754A:A04 ES 129 M00056754B:D09 ES 129 M00056754B:H04 ES 129M00056754D:A05 ES 129 M00056756B:A05 ES 129 M00056756D:B08 ES 129M00056757B:F03 ES 129 M00056758B:C05 ES 129 M00056759A:F11 ES 129M00056759B:G03 ES 129 M00056760D:A04 ES 129 M00056761A:F05 ES 129M00056762C:E05 ES 129 M00056763C:D05 ES 129 M00056764A:E08 ES 129M00056765A:A10 ES 130 M00056765C:E12 ES 130 M00056765D:D10 ES 130M00056766B:A10 ES 130 M00056771C:F12 ES 130 M00056771D:C12 ES 130M00056772D:A04 ES 130 M00056772D:A04 ES 130 M00056772D:E08 ES 130M00056773A:H11 ES 130 M00056774B:A02 ES 130 M00056775D:A07 ES 130M00056775D:C01 ES 130 M00056775D:C08 ES 130 M00056776D:A06 ES 130M00056776D:D09 ES 130 M00056777B:C03 ES 130 M00056777D:B02 ES 130M00056777D:F07 ES 130 M00056779A:E12 ES 130 M00056779D:H10 ES 130M00056779D:H10 ES 130 M00056780D:C02 ES 130 M00056780D:F09 ES 130M00056781C:E12 ES 130 M00056782D:B06 ES 130 M00056783B:G11 ES 130M00056784A:B05 ES 130 M00056785B:F08 ES 130 M00056789A:C04 ES 130M00056789D:E10 ES 130 M00056791D:F12 ES 130 M00056793C:H07 ES 130M00056796A:H05 ES 130 M00056799B:E11 ES 130 M00056802B:H01 ES 130M00056802B:H01 ES 130 M00056804B:E06 ES 130 M00056805D:B09 ES 130M00056808B:B12 ES 130 M00056811A:C04 ES 130 M00056812C:E08 ES 130M00056815A:B01 ES 130 M00056816B:A10 ES 130 M00056817C:C03 ES 130M00056821D:C09 ES 130 M00056822C:G11 ES 130 M00056823A:B05 ES 130M00056823C:A07 ES 131 M00056824B:C10 ES 131 M00056824D:E01 ES 131M00056826A:B12 ES 131 M00056830C:G02 ES 131 M00056833C:C01 ES 131M00056839A:G01 ES 131 M00056839A:G02 ES 131 M00056839C:F01 ES 131M00056840D:H09 ES 131 M00056841D:G09 ES 131 M00056842B:F12 ES 131M00056842B:F12 ES 131 M00056843B:H09 ES 131 M00056844A:E07 ES 131M00056844C:A10 ES 131 M00056848B:C07 ES 131 M00056850B:E11 ES 131M00056850B:E11 ES 131 M00056857B:C09 ES 131 M00056858A:B03 ES 131M00056858B:A12 ES 131 M00056859A:D12 ES 131 M00056860A:F12 ES 131M00056863C:E03 ES 131 M00056864B:H09 ES 131 M00056866B:E05 ES 131M00056868D:E09 ES 131 M00056870A:E10 ES 131 M00056872A:A06 ES 131M00056873C:E06 ES 131 M00056874B:H06 ES 131 M00056874C:D05 ES 131M00056874D:G01 ES 131 M00056879A:E05 ES 131 M00056879B:H11 ES 131M00056879D:A02 ES 131 M00056880D:B04 ES 131 M00056883D:A07 ES 131M00056884B:C06 ES 131 M00056885C:C06 ES 131 M00056886A:C11 ES 131M00056887B:F08 ES 131 M00056892C:A01 ES 131 M00056893B:H06 ES 131M00056894D:G06 ES 131 M00056895B:A07 ES 131 M00056896A:F05 ES 131M00056896A:F10 ES 132 M00056898D:D04 ES 132 M00056901A:A06 ES 132M00056902A:H12 ES 132 M00056909B:E11 ES 132 M00056909C:D09 ES 132M00056911B:F02 ES 132 M00056913B:G10 ES 132 M00056914D:B09 ES 132M00056916C:B02 ES 132 M00056916C:F04 ES 132 M00056921A:C07 ES 132M00056923C:E09 ES 132 M00056924D:B06 ES 132 M00056925D:C07 ES 132M00056939A:F08 ES 132 M00056939D:B02 ES 132 M00056941D:E02 ES 132M00056945A:B11 ES 132 M00056947D:F09 ES 132 M00056949C:F06 ES 132M00056951B:F09 ES 132 M00056952C:A06 ES 132 M00056952D:H04 ES 132M00056953B:A06 ES 132 M00056955B:G09 ES 132 M00056956B:F01 ES 132M00056960A:C05 ES 132 M00056961A:B08 ES 132 M00056961C:G12 ES 132M00056964B:A02 ES 132 M00056966D:A11 ES 132 M00056967A:D02 ES 132M00056967A:E07 ES 132 M00056969B:C08 ES 132 M00056969D:B01 ES 132M00056972A:F05 ES 132 M00056973D:B08 ES 132 M00056974C:F04 ES 132M00056976C:F10 ES 132 M00056977A:G03 ES 132 M00056985B:C05 ES 132M00056986A:F11 ES 132 M00056986D:G01 ES 132 M00056990C:B09 ES 132M00056990D:C11 ES 132 M00056993A:B06 ES 132 M00056993D:D03 ES 132M00056994B:F07 ES 133 M00056994C:C03 ES 133 M00056996D:A12 ES 133M00056997C:H09 ES 133 M00056998A:E08 ES 133 M00057002D:B05 ES 133M00057002D:B06 ES 133 M00057003B:B09 ES 133 M00057005B:C01 ES 133M00057005C:D03 ES 133 M00057007C:B12 ES 133 M00057008C:E09 ES 133M00057011A:D03 ES 133 M00057013B:D01 ES 133 M00057015A:C12 ES 133M00057019C:H02 ES 133 M00057023A:H09 ES 133 M00057024A:E02 ES 133M00057024A:G05 ES 133 M00057024D:H08 ES 133 M00057025C:A08 ES 133M00057027C:G06 ES 133 M00057028D:D09 ES 133 M00057029A:C12 ES 133M00057029D:A06 ES 133 M00057033A:F09 ES 133 M00057035B:C09 ES 133M00057041D:B11 ES 133 M00057044C:F06 ES 133 M00057047B:C02 ES 133M00057049A:G06 ES 133 M00057049C:H05 ES 133 M00057052D:B11 ES 133M00057052D:G09 ES 133 M00057055B:G08 ES 133 M00057055B:G08 ES 133M00057058C:F09 ES 133 M00057059D:F06 ES 133 M00057059D:H09 ES 133M00057060B:A12 ES 133 M00057061C:D04 ES 133 M00057063A:C08 ES 133M00057065C:D04 ES 133 M00057066A:A04 ES 133 M00057070D:B08 ES 133M00057072B:E02 ES 133 M00057073D:A05 ES 133 M00057074D:C09 ES 133M00057074D:C09 ES 134 M00055909B:G01 ES 134 M00055909C:E08 ES 134M00055911B:E06 ES 134 M00055912C:E10 ES 134 M00055912D:C05 ES 134M00055913B:D05 ES 134 M00055919A:A06 ES 134 M00055921A:E03 ES 134M00055921B:B11 ES 134 M00055922A:C02 ES 134 M00055924A:H11 ES 134M00055930A:B08 ES 134 M00055931A:A03 ES 134 M00055931A:C01 ES 134M00055931B:E01 ES 134 M00055936B:E07 ES 134 M00055937B:C02 ES 134M00055941B:B12 ES 134 M00055941B:B12 ES 134 M00055945A:H11 ES 134M00055945B:E10 ES 134 M00055946D:G07 ES 134 M00055951C:C02 ES 134M00055956C:E02 ES 134 M00055958D:F02 ES 134 M00055959D:A12 ES 134M00055966C:A03 ES 134 M00055966C:D06 ES 134 M00055971C:E07 ES 134M00055973A:D04 ES 134 M00055976B:F01 ES 134 M00055979B:B09 ES 134M00055980A:A10 ES 134 M00055981D:A07 ES 134 M00055984C:C02 ES 134M00055985D:D01 ES 134 M00055990C:B05 ES 134 M00055992C:E11 ES 134M00056139D:E04 ES 134 M00056139D:G01 ES 134 M00056140B:H07 ES 134M00056140D:E07 ES 134 M00056141A:D05 ES 134 M00056141D:B09 ES 134M00056143A:E09 ES 134 M00056144B:C09 ES 134 M00056145C:B04 ES 134M00056149C:B01 ES 135 M00056150B:C12 ES 135 M00056153C:D01 ES 135M00056156D:A12 ES 135 M00056160D:A08 ES 135 M00056161D:G04 ES 135M00056162B:F08 ES 135 M00056162B:F08 ES 135 M00056162D:D06 ES 135M00056162D:E09 ES 135 M00056167D:B08 ES 135 M00056169A:F06 ES 135M00056171C:H11 ES 135 M00056171C:H12 ES 135 M00056180B:H09 ES 135M00056184B:D08 ES 135 M00056184C:H03 ES 135 M00056184D:F01 ES 135M00056185D:A03 ES 135 M00056185D:D06 ES 135 M00056186C:F02 ES 135M00056190D:G02 ES 135 M00056192D:E04 ES 135 M00056192D:H02 ES 135M00056195B:C08 ES 135 M00056198A:D07 ES 135 M00056199D:A09 ES 135M00056201C:H08 ES 135 M00056203A:H10 ES 135 M00056204B:A04 ES 135M00056205B:D01 ES 135 M00056206A:E06 ES 136 M00055997C:G11 ES 136M00055999C:G10 ES 136 M00055999D:G06 ES 136 M00056000A:F12 ES 136M00056000C:D09 ES 136 M00056001A:B06 ES 136 M00056001A:B07 ES 136M00056001C:E09 ES 136 M00056003A:E06 ES 136 M00056005B:E05 ES 136M00056005D:C04 ES 136 M00056007A:A11 ES 136 M00056007C:F06 ES 136M00056016D:D06 ES 136 M00056018B:G05 ES 136 M00056020A:D10 ES 136M00056020D:D07 ES 136 M00056028C:F03 ES 136 M00056036D:B06 ES 136M00056037C:B02 ES 136 M00056038D:F04 ES 136 M00056041A:C04 ES 136M00056042A:A01 ES 136 M00056045D:H01 ES 136 M00056050C:A03 ES 136M00056053A:A09 ES 136 M00056053A:D12 ES 136 M00056055A:A07 ES 136M00056055B:B01 ES 136 M00056055C:D03 ES 136 M00056058A:H04 ES 136M00056060B:B10 ES 136 M00056061B:F06 ES 136 M00056066D:H07 ES 136M00056067B:D08 ES 136 M00056074D:G10 ES 136 M00056077D:E06 ES 136M00056077D:E12 ES 136 M00056077D:E12 ES 136 M00056079B:D12 ES 136M00056079B:F07 ES 136 M00056079C:C11 ES 136 M00056081D:B05 ES 136M00056081D:B09 ES 136 M00056082C:F06 ES 136 M00056085D:H11 ES 136M00056094A:H07 ES 136 M00056098A:H01 ES 136 M00056099B:G09 ES 136M00056099B:H11 ES 136 M00056099B:H11 ES 136 M00056103A:D12 ES 136M00056103C:H12 ES 136 M00056107B:E06 ES 136 M00056108D:B12 ES 136M00056108D:B12 ES 136 M00056110C:D09 ES 136 M00056111D:H02 ES 136M00056112A:H02 ES 136 M00056114C:C06 ES 136 M00056125B:D09 ES 136M00056128C:B10 ES 136 M00056131B:C12 ES 136 M00056133D:D09 ES 136M00056136A:B11

The above material has been deposited with the American Type CultureCollection, Rockville, Md., under the accession number indicated. Thesedeposits will be maintained under the terms of the Budapest Treaty onthe International Recognition of the Deposit of Microorganisms for thePurposes of Patent Procedure. The deposit will be maintained for aperiod of at least 30 years following issuance of this patent, or forthe enforceable life of the patent, whichever is greater. Upon thegranting of a patent, all restrictions on the availability to the publicof the deposited material will be irrevocably removed.

The deposits described herein are provided merely as convenience tothose of skill in the art, and is not an admission that a deposit isrequired under 35 U.S.C. §112. The sequence of the polynucleotidescontained within the deposited material, as well as the amino acidsequence of the polypeptides encoded thereby, are incorporated herein byreference and are controlling in the event of any conflict with thewritten description of sequences herein. A license may be required tomake, use, or sell the deposited material, and no such license isgranted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones. Where theATCC deposit is composed of a pool of cDNA clones or a library of cDNAclones, the deposit was prepared by first transfecting each of theclones into separate bacterial cells. The clones in the pool or librarywere then deposited as a pool of equal mixtures in the compositedeposit. Particular clones can be obtained from the composite depositusing methods well known in the art. For example, a bacterial cellcontaining a particular clone can be identified by isolating singlecolonies, and identifying colonies containing the specific clone throughstandard colony hybridization techniques, using an oligonucleotide probeor probes designed to specifically hybridize to a sequence of the cloneinsert (e.g., a probe based upon unmasked sequence of the encodedpolynucleotide having the indicated SEQ ID NO). The probe should bedesigned to have a T_(m) of approximately 80° C. (assuming 2° C. foreach A or T and 4° C. for each G or C). Positive colonies can then bepicked, grown in culture, and the recombinant clone isolated.Alternatively, probes designed in this manner can be used to PCR toisolate a nucleic acid molecule from the pooled clones according tomethods well known in the art, e.g., by purifying the cDNA from thedeposited culture pool, and using the probes in PCR reactions to producean amplified product having the corresponding desired polynucleotidesequence.

Example 77 Source of Biological Materials and Overview of NovelPolynucleotides Expressed by the Biological Materials

cDNA libraries were constructed from mRNA isolated from the GRRpz or andWOca cells, which were provided by Dr. Donna M. Peehl, Department ofMedicine, Stanford University School of Medicine. GRRpz cells wereprimary cells derived from normal prostate epithelium. The WOca cellswere prostate epithelial cells derived from prostate cancer GleasonGrade 4+4. Polynucleotides expressed by these cells were isolated andanalyzed; the sequences of these polynucleotides were about 275-300nucleotides in length.

The sequences of the isolated polynucleotides were first masked toeliminate low complexity sequences using the XBLAST masking program(Claverie “Effective Large-Scale Sequence Similarity Searches,” In:Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed.,Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); seeparticularly Claverie, in “Automated DNA Sequencing and AnalysisTechniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, SanDiego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally,masking does not influence the final search results, except to eliminatesequences of relative little interest due to their low complexity, andto eliminate multiple “hits” based on similarity to repetitive regionscommon to multiple sequences, e.g., Alu repeats. The remaining sequenceswere then used in a BLASTN vs. GenBank search; sequences that exhibitedgreater than 70% overlap, 99% identity, and a p value of less than1×10⁻⁴⁰ were discarded. Sequences from this search also were discardedif the inclusive parameters were met, but the sequence was ribosomal orvector-derived.

The resulting sequences from the previous search were classified intothree groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP(non-redundant proteins) database search: (1) unknown (no hits in theGenBank search), (2) weak similarity (greater than 45% identity and pvalue of less than 1×10⁻⁵), and (3) high similarity (greater than 60%overlap, greater than 80% identity, and p value less than 1×10⁻⁵).Sequences having greater than 70% overlap, greater than 99% identity,and p value of less than 1×10⁻⁴⁰ were discarded.

The remaining sequences were classified as unknown (no hits), weaksimilarity, and high similarity (parameters as above). Two searches wereperformed on these sequences. First, a BLAST vs. EST database search wasperformed and sequences with greater than 99% overlap, greater than 99%similarity and a p value of less than 1×10⁻⁴⁰ were discarded. Sequenceswith a p value of less than 1×10⁻⁶⁵ when compared to a database sequenceof human origin were also excluded. Second, a BLASTN vs. Patent GeneSeqdatabase was performed and sequences having greater than 99% identity, pvalue less than 1×10⁻⁴⁰, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rulesand redundancies in the dataset. Sequences with a p value of less than1×10⁻¹¹¹ in relation to a database sequence of human origin werespecifically excluded. The final result provided the 316 sequenceslisted as SEQ ID NOS:15667-15982 in the accompanying Sequence Listingand summarized in Table 120 (inserted prior to claims). Each identifiedpolynucleotide represents sequence from at least a partial mRNAtranscript. Many of the sequences include the sequence ggcacgag at the5′ end; this sequence is a sequencing artifact and not part of thesequence of the polynucleotides of the invention.

Table 120 provides: 1) the SEQ ID NO (“SEQ ID”) assigned to eachsequence for use in the present specification; 2) the ClusterIdentification No. (“CLUSTER”); 3) the sequence name (“SEQ NAME”) usedas an internal identifier of the sequence; 4) the orientation of thesequence (“ORIENT”); 5) the name assigned to the clone from which thesequence was isolated (“CLONE ID”); and the name of the library fromwhich the sequence was isolated (“LIBRARY”). CH22PRC indicates thesequence was isolated from Library 22; CH21PRN indicates the sequencewas isolated from Library 21. A description of the libraries is providedin Table 122 below. Because the provided polynucleotides representpartial mRNA transcripts, two or more polynucleotides of the inventionmay represent different regions of the same mRNA transcript and the samegene. Thus, if two or more SEQ ID NOS: are identified as belonging tothe same clone, then either sequence can be used to obtain thefull-length mRNA or gene.

Example 78 Results of Public Database Search to Identify Function ofGene Products

SEQ ID NOS: 15667-15982 were translated in all three reading frames, andthe nucleotide sequences and translated amino acid sequences used asquery sequences to search for homologous sequences in either the GenBank(nucleotide sequences) or Non-Redundant Protein (amino acid sequences)databases. Query and individual sequences were aligned using the BLAST2.0 programs, available over the world wide web at a saite sponsored bythe National Center for Biotechnology Information, which is supported bythe National Library of Medicine and the National Institutes of Health(see also Altschul, et al. Nucleic Acids Res. (1997) 25:3389-3402). Thesequences were masked to various extents to prevent searching ofrepetitive sequences or poly-A sequences, using the XBLAST program formasking low complexity as described above in Example 77.

Table 121 (inserted before the claims) provide the alignment summarieshaving a p value of 1×10⁻² or less indicating substantial homologybetween the sequences of the present invention and those of theindicated public databases. Specifically, Table 121 provides the SEQ IDNO of the query sequence, the accession number of the GenBank databaseentry of the homologous sequence, and the p value of the alignment.Table 121 also provides the SEQ ID NO of the query sequence, theaccession number of the Non-Redundant Protein database entry of thehomologous sequence, and the p value of the alignment. The alignmentsprovided in Table 121 are the best available alignment to a DNA or aminoacid sequence at a time just prior to filing of the presentspecification. The activity of the polypeptide encoded by the SEQ ID NOSlisted in Table 121 can be extrapolated to be substantially the same orsubstantially similar to the activity of the reported nearest neighboror closely related sequence. The accession number of the nearestneighbor is reported, providing a publicly available reference to theactivities and functions exhibited by the nearest neighbor. The publicinformation regarding the activities and functions of each of thenearest neighbor sequences is incorporated by reference in thisapplication. Also incorporated by reference is all publicly availableinformation regarding the sequence, as well as the putative and actualactivities and functions of the nearest neighbor sequences listed inTable 121 and their related sequences. The search program and databaseused for the alignment, as well as the calculation of the p value arealso indicated.

Full length sequences or fragments of the polynucleotide sequences ofthe nearest neighbors can be used as probes and primers to identify andisolate the full length sequence of the corresponding polynucleotide.The nearest neighbors can indicate a tissue or cell type to be used toconstruct a library for the full-length sequences of the correspondingpolynucleotides. TABLE 120 SEQ ID CLUSTER SEQ NAME ORIENT CLONE IDLIBRARY 15667 819545 RTA22200265F.k.06.1.P.Seq F M00064554D:A03 CH22PRC15668 377944 RTA22200251F.j.02.1.P.Seq F M00063482A:A08 CH21PRN 15669818497 RTA22200252F.a.13.1.P.Seq F M00063514C:D03 CH21PRN 15670 819498RTA22200252F.n.05.1.P.Seq F M00063638C:G12 CH21PRN 15671 455465RTA22200264F.e.16.1.P.Seq F M00064454A:H10 CH22PRC 15672 819069RTA22200255F.f.01.1.P.Seq F M00063940D:F09 CH21PRN 15673 672003RTA22200265F.b.09.1.P.Seq F M00064517C:F11 CH22PRC 15674 728115RTA22200253F.o.24.1.P.Seq F M00063838B:G08 CH21PRN 15675 372700RTA22200260F.b.20.1.P.Seq F M00063580C:A06 CH22PRC 15676 818056RTA22200266F.c.13.1.P.Seq F M00064593D:C01 CH22PRC 15677 818497RTA22200255F.a.17.1.P.Seq F M00063920D:H02 CH21PRN 15678 729832RTA22200267F.l.21.1.P.Seq F M00064714A:G03 CH22PRC 15679 505514RTA22200251F.b.21.1.P.Seq F M00063158A:A01 CH21PRN 15680 376488RTA22200254F.c.05.1.P.Seq F M00063852B:D08 CH21PRN 15681 376488RTA22200260F.b.09.1.P.Seq F M00063578C:A06 CH22PRC 15682 748572RTA22200254F.c.07.1.P.Seq F M00063852D:F07 CH21PRN 15683 549934RTA22200253F.k.18.1.P.Seq F M00063801B:D04 CH21PRN 15684 819069RTA22200255F.e.24.1.P.Seq F M00063940D:F09 CH21PRN 15685 817618RTA22200253F.n.16.1.P.Seq F M00063828D:E05 CH21PRN 15686 124396RTA22200263F.a.11.2.P.Seq F M00064375B:G07 CH22PRC 15687 404375RTA22200260F.m.08.1.P.Seq F M00063967D:G02 CH22PRC 15688 391820RTA22200261F.f.02.1.P.Seq F M00064000B:C03 CH22PRC 15689 672003RTA22200267F.i.06.1.P.Seq F M00064693D:F08 CH22PRC 15690 830620RTA22200263F.n.09.1.P.Seq F M00064424B:C12 CH22PRC 15691 450399RTA22200251F.f.23.1.P.Seq F M00063467D:H07 CH21PRN 15692 450982RTA22200261F.n.18.1.P.Seq F M00064307B:G02 CH22PRC 15693 819894RTA22200264F.h.18.1.P.Seq F M00064467B:D06 CH22PRC 15694 379302RTA22200257F.j.02.3.P.Seq F M00064178C:C04 CH21PRN 15695 379746RTA22200256F.e.16.1.P.Seq F M00064086C:E01 CH21PRN 15696 124863RTA22200265F.m.06.1.P.Seq F M00064564A:C02 CH22PRC 15697 379154RTA22200257F.c.11.1.P.Seq F M00064151B:C07 CH21PRN 15698 830620RTA22200262F.l.23.1.P.Seq F M00064358C:D09 CH22PRC 15699 389409RTA22200266F.l.24.1.P.Seq F M00064631A:C07 CH22PRC 15700 397284RTA22200262F.i.22.1.P.Seq F M00064346C:B09 CH22PRC 15701 819440RTA22200264F.e.19.1.P.Seq F M00064454C:B06 CH22PRC 15702 389409RTA22200266F.m.01.1.P.Seq F M00064631A:C07 CH22PRC 15703 518848RTA22200265F.n.15.1.P.Seq F M00064571C:C04 CH22PRC 15704 830620RTA22200263F.a.21.1.P.Seq F M00064376A:A05 CH22PRC 15705 379154RTA22200256F.f.20.1.P.Seq F M00064090D:D09 CH21PRN 15706 818544RTA22200256F.h.04.1.P.Seq F M00064105B:A03 CH21PRN 15707 817375RTA22200251F.a.15.1.P.Seq F M00063152C:B07 CH21PRN 15708 455264RTA22200259F.e.23.1.P.Seq F M00063539C:C11 CH22PRC 15709 817503RTA22200266F.k.11.1.P.Seq F M00064624D:C09 CH22PRC 15710 377696RTA22200256F.d.21.1.P.Seq F M00064082D:D10 CH21PRN 15711 375596RTA22200261F.h.10.1.P.Seq F M00064009A:C01 CH22PRC 15712 817689RTA22200263F.h.05.1.P.Seq F M00064399A:E01 CH22PRC 15713 831867RTA22200262F.i.15.2.P.Seq F M00064345A:A03 CH22PRC 15714 830085RTA22200261F.k.14.1.P.Seq F M00064293D:B12 CH22PRC 15715 389627RTA22200264F.c.10.1.P.Seq F M00064447B:C06 CH22PRC 15716 397284RTA22200259F.k.09.1.P.Seq F M00063555B:D01 CH22PRC 15717 380063RTA22200261F.j.02.1.P.Seq F M00064014D:H05 CH22PRC 15718 830931RTA22200266F.m.23.1.P.Seq F M00064633C:A03 CH22PRC 15719 819321RTA22200257F.l.03.3.P.Seq F M00064194C:D02 CH21PRN 15720 475587RTA22200261F.c.01.1.P.Seq F M00063990A:D05 CH22PRC 15721 819046RTA22200255F.a.18.1.P.Seq F M00063920D:H05 CH21PRN 15722 817477RTA22200253F.g.21.1.P.Seq F M00063784A:H12 CH21PRN 15723 475587RTA22200261F.b.24.1.P.Seq F M00063990A:D05 CH22PRC 15724 728115RTA22200253F.p.01.1.P.Seq F M00063838B:G08 CH21PRN 15725 389627RTA22200260F.i.24.1.P.Seq F M00063957A:E02 CH22PRC 15726 403453RTA22200256F.i.24.1.P.Seq F M00064113B:C04 CH21PRN 15727 508525RTA22200255F.d.10.1.P.Seq F M00063931B:F07 CH21PRN 15728 819525RTA22200261F.n.20.1.P.Seq F M00064307C:G03 CH22PRC 15729 817618RTA22200255F.i.03.1.P.Seq F M00064025D:H12 CH21PRN 15730 819403RTA22200254F.h.14.1.P.Seq F M00063888D:D05 CH21PRN 15731 553242RTA22200254F.g.20.1.P.Seq F M00063886A:B06 CH21PRN 15732 817417RTA22200255F.a.10.1.P.Seq F M00063919C:E07 CH21PRN 15733 817618RTA22200252F.f.13.1.P.Seq F M00063604A:B11 CH21PRN 15734 611440RTA22200262F.e.04.2.P.Seq F M00064328B:H09 CH22PRC 15735 817375RTA22200260F.m.06.1.P.Seq F M00063967C:A12 CH22PRC 15736 213577RTA22200255F.i.23.1.P.Seq F M00064033C:C11 CH21PRN 15737 820061RTA22200265F.p.10.1.P.Seq F M00064579D:E11 CH22PRC 15738 455264RTA22200259F.m.06.1.P.Seq F M00063559D:G03 CH22PRC 15739 455264RTA22200255F.o.23.1.P.Seq F M00064059A:C11 CH21PRN 15740 380331RTA22200255F.b.19.1.P.Seq F M00063926A:H04 CH21PRN 15741 380331RTA22200252F.b.19.1.P.Seq F M00063518D:A01 CH21PRN 15742 817455RTA22200267F.o.01.1.P.Seq F M00064723D:H03 CH22PRC 15743 423967RTA22200252F.a.20.1.P.Seq F M00063515B:H02 CH21PRN 15744 220584RTA22200261F.m.14.1.P.Seq F M00064302A:D10 CH22PRC 15745 817688RTA22200251F.e.20.1.P.Seq F M00063462D:D07 CH21PRN 15746 549934RTA22200253F.n.10.1.P.Seq F M00063826A:D03 CH21PRN 15747 819149RTA22200255F.e.16.1.P.Seq F M00063938B:H07 CH21PRN 15748 817455RTA22200267F.n.24.1.P.Seq F M00064723D:H03 CH22PRC 15749 377696RTA22200251F.j.03.1.P.Seq F M00063482A:F07 CH21PRN 15750 830146RTA22200260F.b.07.1.P.Seq F M00063578B:E02 CH22PRC 15751 194490RTA22200264F.l.07.1.P.Seq F M00064481C:F03 CH22PRC 15752 819460RTA22200257F.m.15.3.P.Seq F M00064200D:E08 CH21PRN 15753 819018RTA22200257F.p.01.3.P.Seq F M00064212D:E04 CH21PRN 15754 830620RTA22200259F.p.24.1.P.Seq F M00063571B:G03 CH22PRC 15755 141079RTA22200262F.k.19.1.P.Seq F M00064354A:A10 CH22PRC 15756 376588RTA22200256F.e.04.1.P.Seq F M00064083D:E05 CH21PRN 15757 380604RTA22200264F.g.05.1.P.Seq F M00064460C:B01 CH22PRC 15758 413138RTA22200260F.b.05.1.P.Seq F M00063577C:C02 CH22PRC 15759 818544RTA22200265F.e.12.1.P.Seq F M00064527A:H07 CH22PRC 15760 647435RTA22200257F.h.08.1.P.Seq F M00064172C:A02 CH21PRN 15761 551785RTA22200266F.c.09.1.P.Seq F M00064593A:A05 CH22PRC 15762 17092RTA22200261F.f.17.1.P.Seq F M00064002C:F06 CH22PRC 15763 818326RTA22200251F.i.06.1.P.Seq F M00063478C:D01 CH21PRN 15764 377944RTA22200262F.e.03.2.P.Seq F M00064328B:H04 CH22PRC 15765 745559RTA22200262F.m.04.1.P.Seq F M00064359B:H12 CH22PRC 15766 818326RTA22200265F.d.08.1.P.Seq F M00064524A:A09 CH22PRC 15767 379879RTA22200264F.b.23.1.P.Seq F M00064446A:D11 CH22PRC 15768 819640RTA22200257F.f.24.1.P.Seq F M00064165A:B12 CH21PRN 15769 818326RTA22200265F.a.14.1.P.Seq F M00064514D:F11 CH22PRC 15770 243524RTA22200265F.g.04.1.P.Seq F M00064532D:G06 CH22PRC 15771 43995RTA22200261F.l.02.1.P.Seq F M00064294D:F01 CH22PRC 15772 597854RTA22200262F.g.06.2.P.Seq F M00064337D:F01 CH22PRC 15773 268290RTA22200260F.p.14.1.P.Seq F M00063981D:A06 CH22PRC 15774 818043RTA22200256F.p.10.2.P.Seq F M00064138A:F11 CH21PRN 15775 830930RTA22200267F.b.03.1.P.Seq F M00064652B:D09 CH22PRC 15776 389627RTA22200260F.j.01.1.P.Seq F M00063957A:E02 CH22PRC 15777 378730RTA22200260F.i.07.1.P.Seq F M00063955C:F07 CH22PRC 15778 819037RTA22200260F.n.09.1.P.Seq F M00063972C:E10 CH22PRC 15779 830397RTA22200261F.g.14.1.P.Seq F M00064005D:A08 CH22PRC 15780 450247RTA22200261F.e.10.1.P.Seq F M00063998C:E09 CH22PRC 15781 819273RTA22200252F.b.09.1.P.Seq F M00063517A:A04 CH21PRN 15782 587779RTA22200257F.i.11.3.P.Seq F M00064175B:B09 CH21PRN 15783 818639RTA22200256F.j.09.1.P.Seq F M00064115B:E12 CH21PRN 15784 615617RTA22200261F.o.13.1.P.Seq F M00064309C:H09 CH22PRC 15785 79309RTA22200257F.j.13.3.P.Seq F M00064180A:G03 CH21PRN 15786 748994RTA22200261F.o.20.1.P.Seq F M00064310C:A10 CH22PRC 15787 818682RTA22200258F.h.07.1.P.Seq F M00064271B:D03 CH21PRN 15788 373061RTA22200253F.j.09.1.P.Seq F M00063795C:D09 CH21PRN 15789 484413RTA22200253F.g.09.1.P.Seq F M00063781B:B10 CH21PRN 15790 819273RTA22200258F.h.04.1.P.Seq F M00064270B:B03 CR21PRN 15791 569532RTA22200252F.h.18.1.P.Seq F M00063613D:C11 CH21PRN 15792 170313RTA22200255F.g.20.1.P.Seq F M00063949D:A05 CH21PRN 15793 818682RTA22200253F.p.14.1.P.Seq F M00063841A:B09 CH21PRN 15794 377188RTA22200255F.l.06.1.P.Seq F M00064043D:C09 CH21PRN 15795 518848RTA22200257F.j.22.3.P.Seq F M00064186C:B03 CH21PRN 15796 45592RTA22200259F.l.08.1.P.Seq F M00063557D:C07 CH22PRC 15797 819273RTA22200255F.n.19.1.P.Seq F M00064053C:G04 CH21PRN 15798 397284RTA22200251F.a.06.1.P.Seq F M00063151D:B10 CH21PRN 15799 818326RTA22200258F.e.14.1.P.Seq F M00064260C:E05 CR21PRN 15800 819037RTA22200251F.c.15.1.P.Seq F M00063452A:F08 CH21PRN 15801 817417RTA22200253F.m.14.1.P.Seq F M00063818C:A09 CH21PRN 15802 819640RTA22200254F.i.11.1.P.Seq F M00063891A:F11 CH21PRN 15803 818771RTA22200254F.i.19.1.P.Seq F M00063892B:G02 CR21PRN 15804 389627RTA22200254F.k.10.1.P.Seq F M00063898A:A10 CH21PRN 15805 379067RTA22200260F.e.20.1.P.Seq F M00063593A:D03 CH22PRC 15806 818544RTA22200251F.f.02.1.P.Seq F M00063463D:B05 CH21PRN 15807 819440RTA22200251F.j.22.1.P.Seq F M00063485A:E05 CH21PRN 15808 817417RTA22200251F.k.10.1.P.Seq F M00063487C:C02 CH21PRN 15809 385307RTA22200262F.k.11.1.P.Seq F M00064352C:H01 CH22PRC 15810 611440RTA22200263F.d.24.2.P.Seq F M00064386B:C02 CH22PRC 15811 376056RTA22200259F.e.16.1.P.Seq F M00063538D:B01 CH22PRC 15812 611440RTA22200263F.d.24.1.P.Seq F M00064386B:C02 CH22PRC 15813 820061RTA22200264F.f.09.1.P.Seq F M00064457D:C09 CH22PRC 15814 617825RTA22200264F.p.06.1.P.Seq F M00064508A:B09 CH22PRC 15815 819440RTA22200257F.h.17.1.P.Seq F M00064173B:E01 CH21PRN 15816 819145RTA22200266F.m.08.1.P.Seq F M00064631C:H11 CH22PRC 15817 817653RTA22200265F.p.07.1.P.Seq F M00064579A:C06 CH22PRC 15818 611440RTA22200263F.e.01.1.P.Seq F M00064386B:C02 CH22PRC 15819 375958RTA22200264F.j.22.1.P.Seq F M00064476D:C04 CH22PRC 15820 611440RTA22200257F.a.20.1.P.Seq F M00064144D:A07 CH21PRN 15821 831049RTA22200266F.o.13.1.P.Seq F M00064637B:F03 CH22PRC 15822 818162RTA22200266F.g.18.1.P.Seq F M00064610D:H01 CH22PRC 15823 553200RTA22200263F.p.02.1.P.Seq F M00064429D:B07 CH22PRC 15824 139677RTA22200254F.o.07.1.P.Seq F M00063910D:A12 CH21PRN 15825 139677RTA22200252F.c.11.1.P.Seq F M00063520D:E11 CH21PRN 15826 397284RTA22200262F.i.22.2.P.Seq F M00064346C:B09 CH22PRC 15827 385810RTA22200256F.m.04.2.P.Seq F M00064126C:F12 CH21PRN 15828 404624RTA22200261F.e.07.1.P.Seq F M00063997C:B12 CH22PRC 15829 375958RTA22200262F.b.14.2.P.Seq F M00064322C:A10 CH22PRC 15830 616555RTA22200265F.b.24.1.P.Seq F M00064520A:E04 CH22PRC 15831 616555RTA22200265F.c.01.1.P.Seq F M00064520A:E04 CH22PRC 15832 295694RTA22200260F.o.20.1.P.Seq F M00063978B:B06 CH22PRC 15833 36113RTA22200265F.e.06.1.P.Seq F M00064526D:F05 CH22PRC 15834 831812RTA22200263F.f.05.1.P.Seq F M00064390A:C05 CH22PRC 15835 817653RTA22200252F.g.23.1.P.Seq F M00063610D:C11 CH21PRN 15836 397284RTA22200252F.m.15.1.P.Seq F M00063636A:E01 CH21PRN 15837 817979RTA22200253F.p.15.1.P.Seq F M00063841A:E08 CH21PRN 15838 817653RTA22200255F.m.18.1.P.Seq F M00064048C:G12 CH21PRN 15839 611440RTA22200253F.f.03.1.P.Seq F M00063774A:D09 CH21PRN 15840 386014RTA22200261F.f.06.1.P.Seq F M00064001A:B03 CH22PRC 15841 549981RTA22200255F.b.10.1.P.Seq F M00063925B:F04 CH21PRN 15842 193373RTA22200255F.l.21.1.P.Seq F M00064046A:G02 CH21PRN 15843 400619RTA22200255F.g.14.1.P.Seq F M00063947D:D01 CH21PRN 15844 831149RTA22200261F.o.21.1.P.Seq F M00064310D:F03 CH22PRC 15845 36113RTA22200255F.d.16.1.P.Seq F M00063932D:G08 CH21PRN 15846 817503RTA22200253F.l.16.1.P.Seq F M00063805D:E05 CH21PRN 15847 376588RTA22200260F.i.11.1.P.Seq F M00063955D:F05 CH22PRC 15848 141079RTA22200252F.f.23.1.P.Seq F M00063606C:B04 CH21PRN 15849 818063RTA22200253F.p.04.1.P.Seq F M00063839A:F01 CH21PRN 15850 455264RTA22200253F.n.14.1.P.Seq F M00063828A:H12 CH21PRN 15851 189234RTA22200251F.f.17.1.P.Seq F M00063466C:C11 CH21PRN 15852 295694RTA22200265F.j.05.1.P.Seq F M00064550A:A07 CH22PRC 15853 648679RTA22200260F.f.06.1.P.Seq F M00063594B:H07 CH22PRC 15854 830930RTA22200264F.e.10.1.P.Seq F M00064452D:E11 CH22PRC 15855 818497RTA22200256F.d.07.1.P.Seq F M00064079C:A10 CH21PRN 15856 373928RTA22200256F.d.19.1.P.Seq F M00064082A:A08 CH21PRN 15857 385307RTA22200263F.j.12.1.P.Seq F M00064406B:H06 CH22PRC 15858 403453RTA22200266F.e.10.1.P.Seq F M00064601D:B05 CH22PRC 15859 730318RTA22200264F.c.09.1.P.Seq F M00064447B:A07 CH22PRC 15860 44183RTA22200271F.a.01.1.P.Seq F M00021929A:D03 CH03MAH 15861 373928RTA22200255F.d.22.1.P.Seq F M00063934B:E04 CH21PRN 15862 404624RTA22200255F.d.23.1.P.Seq F M00063934C:C10 CH21PRN 15863 403173RTA22200253F.a.21.1.P.Seq F M00063685A:C02 CH21PRN 15864 372700RTA22200253F.c.06.1.P.Seq F M00063689D:E12 CH21PRN 15865 374343RTA22200261F.h.04.1.P.Seq F M00064008A:B01 CH22PRC 15866 597854RTA22200255F.j.03.1.P.Seq F M00064033D:B01 CH21PRN 15867 817417RTA22200255F.a.23.1.P.Seq F M00063922B:A12 CH21PRN 15868 818497RTA22200257F.k.05.3.P.Seq F M00064188B:G08 CH21PRN 15869 377696RTA22200255F.f.15.1.P.Seq F M00063943B:G12 CH21PRN 15870 379105RTA22200252F.n.19.1.P.Seq F M00063642B:A08 CH21PRN 15871 831188RTA22200267F.o.02.1.P.Seq F M00064723D:H11 CH22PRC 15872 376056RTA22200253F.m.09.1.P.Seq F M00063810C:E03 CH21PRN 15873 124863RTA22200255F.n.15.1.P.Seq F M00064053B:D09 CH21PRN 15874 376056RTA22200254F.i.03.1.P.Seq F M00063890A:F11 CH21PRN 15875 831812RTA22200266F.j.10.1.P.Seq F M00064620C:D01 CH22PRC 15876 141079RTA22200260F.i.14.1.P.Seq F M00063956A:F05 CH22PRC 15877 19148RTA22200265F.o.18.1.P.Seq F M00064577C:B12 CH22PRC 15878 124396RTA22200252F.a.14.1.P.Seq F M00063514C:E08 CH21PRN 15879 831026RTA22200265F.c.03.1.P.Seq F M00064520A:F08 CH22PRC 15880 819037RTA22200263F.i.23.1.P.Seq F M00064405B:C04 CH22PRC 15881 380207RTA22200263F.i.19.1.P.Seq F M00064404C:G05 CH22PRC 15882 819460RTA22200255F.c.13.1.P.Seq F M00063928A:G09 CH21PRN 15883 379067RTA22200253F.g.23.1.P.Seq F M00063784C:E10 CH21PRN 15884 403173RTA22200252F.p.23.1.P.Seq F M00063682A:C04 CH21PRN 15885 3856RTA22200269F.a.05.1.P.Seq F M00003773D:H02 CH01COH 15886 378551RTA22200263F.d.17.1.P.Seq F M00064385D:C11 CH22PRC 15887 456089RTA22200272F.a.09.1.P.Seq F M00043134A:A05 CH19COP 15888 549981RTA22200267F.a.22.1.P.Seq F M00064650B:B07 CH22PRC 15889 378551RTA22200265F.m.21.1.P.Seq F M00064568A:H06 CH22PRC 15890 819201RTA22200256F.n.23.2.P.Seq F M00064132B:B07 CH21PRN 15891 374826RTA22200251F.c.20.1.P.Seq F M00063453B:F08 CH21PRN 15892 389409RTA22200253F.l.23.1.P.Seq F M00063807A:D12 CH21PRN 15893 819149RTA22200260F.a.17.1.P.Seq F M00063575B:G02 CH22PRC 15894 389409RTA22200255F.e.18.1.P.Seq F M00063939C:D06 CH21PRN 15895 818165RTA22200254F.h.15.1.P.Seq F M00063888D:F02 CH21PRN 15896 817757RTA22200252F.i.15.1.P.Seq F M00063617D:F09 CH21PRN 15897 553242RTA22200263F.i.20.1.P.Seq F M00064404D:A06 CH22PRC 15898 385615RTA22200265F.b.08.1.P.Seq F M00064517B:F10 CH22PRC 15899 819102RTA22200258F.h.19.1.P.Seq F M00064272C:G01 CH21PRN 15900 817757RTA22200255F.o.16.1.P.Seq F M00064057C:H10 CH21PRN 15901 385615RTA22200265F.b.07.1.P.Seq F M00064517B:F04 CH22PRC 15902 385615RTA22200253F.l.06.1.P.Seq F M00063804C:A11 CH21PRN 15903 827355RTA22200266F.n.23.1.P.Seq F M00064636B:A04 CH22PRC 15904 817629RTA22200259F.a.13.1.P.Seq F M00063165A:C09 CH22PRC 15905 817514RTA22200260F.h.02.1.P.Seq F M00063600C:C09 CH22PRC 15906 817514RTA22200252F.p.21.1.P.Seq F M00063681B:C02 CH21PRN 15907 680563RTA22200265F.f.13.1.P.Seq F M00064530B:H02 CH22PRC 15908 827355RTA22200255F.e.20.1.P.Seq F M00063939C:H01 CH21PRN 15909 377286RTA22200254F.a.04.1.P.Seq F M00063843B:D07 CH21PRN 15910 680563RTA22200258F.g.18.1.P.Seq F M00064268D:G03 CH21PRN 15911 819156RTA22200255F.h.06.1.P.Seq F M00064021D:H01 CH21PRN 15912 220584RTA22200261F.f.22.1.P.Seq F M00064003B:C10 CH22PRC 15913 616555RTA22200263F.o.12.1.P.Seq F M00064428B:A12 CH22PRC 15914 819498RTA22200254F.o.14.1.P.Seq F M00063912A:D06 CH21PRN 15915 817508RTA22200257F.h.01.1.P.Seq F M00064171D:E05 CH21PRN 15916 817690RTA22200257F.e.05.1.P.Seq F M00064159A:H03 CH21PRN 15917 819156RTA22200256F.h.13.1.P.Seq F M00064106C:G03 CH21PRN 15918 830904RTA22200266F.j.12.1.P.Seq F M00064620D:G05 CH22PRC 15919 819498RTA22200253F.b.04.1.P.Seq F M00063686B:E07 CH21PRN 15920 817508RTA22200257F.g.24.1.P.Seq F M00064171D:E05 CH21PRN 15921 817508RTA22200252F.a.19.1.P.Seq F M00063515B:F06 CH21PRN 15922 831160RTA22200267F.h.01.1.P.Seq F M00064690A:C04 CH22PRC 15923 817762RTA22200252F.k.13.1.P.Seq F M00063627C:F06 CH21PRN 15924 377286RTA22200266F.k.07.1.P.Seq F M00064624C:B03 CH22PRC 15925 831160RTA22200267F.g.24.1.P.Seq F M00064690A:C04 CH22PRC 15926 819994RTA22200256F.k.11.1.P.Seq F M00064119C:D12 CH21PRN 15927 819994RTA22200256F.k.09.1.P.Seq F M00064119B:H10 CH21PRN 15928 373298RTA22200259F.c.19.1.P.Seq F M00063533A:C12 CH22PRC 15929 819894RTA22200256F.m.03.2.P.Seq F M00064126C:C02 CH21PRN 15930 372718RTA22200260F.b.22.1.P.Seq F M00063580D:B06 CH22PRC 15931 827355RTA22200262F.l.20.1.P.Seq F M00064358A:G03 CH22PRC 15932 819894RTA22200255F.d.09.1.P.Seq F M00063931B:E10 CH21PRN 15933 827355RTA22200266F.e.07.1.P.Seq F M00064601C:G07 CH22PRC 15934 372718RTA22200256F.l.03.1.P.Seq F M00064122C:B06 CH21PRN 15935 647435RTA22200251F.b.10.1.P.Seq F M00063156D:H10 CH21PRN 15936 450262RTA22200265F.a.10.1.P.Seq F M00064514A:G10 CH22PRC 15937 484703RTA22200255F.i.20.1.P.Seq F M00064032D:G04 CH21PRN 15938 819498RTA22200256F.f.12.1.P.Seq F M00064089B:F09 CH21PRN 15939 406043RTA22200263F.i.12.1.P.Seq F M00064404A:B05 CH22PRC 15940 817500RTA22200255F.f.24.1.P.Seq F M00063945A:C03 CH21PRN 15941 818180RTA22200264F.o.18.1.P.Seq F M00064506A:C07 CH22PRC 15942 818143RTA22200251F.a.03.1.P.Seq F M00063151A:G06 CH21PRN 15943 819756RTA22200267F.a.18.1.P.Seq F M00064649A:E04 CH22PRC 15944 406908RTA22200257F.i.18.3.P.Seq F M00064176D:H10 CH21PRN 15945 124863RTA22200256F.o.21.2.P.Seq F M00064136C:D12 CH21PRN 15946 429009RTA22200257F.e.24.1.P.Seq F M00064161B:G04 CH21PRN 15947 402586RTA22200257F.i.24.3.P.Seq F M00064178B:A05 CH21PRN 15948 400475RTA22200254F.i.04.1.P.Seq F M00063890A:H04 CH21PRN 15949 403453RTA22200264F.d.12.1.P.Seq F M00064450C:E07 CH22PRC 15950 383021RTA22200259F.d.06.1.P.Seq F M00063534C:A02 CH22PRC 15951 394913RTA22200254F.p.10.1.P.Seq F M00063915C:E01 CH21PRN 15952 831361RTA22200263F.k.19.1.P.Seq F M00064414D:D06 CH22PRC 15953 646020RTA22200267F.n.21.1.P.Seq F M00064723C:H04 CH22PRC 15954 831361RTA22200263F.l.03.1.P.Seq F M00064415B:G03 CH22PRC 15955 831580RTA22200261F.f.18.1.P.Seq F M00064002C:H09 CH22PRC 15956 402586RTA22200257F.j.01.3.P.Seq F M00064178B:A05 CH21PRN 15957 400475RTA22200262F.j.21.1.P.Seq F M00064349D:H01 CH22PRC 15958 818937RTA22200262F.h.14.2.P.Seq F M00064341A:C02 CH22PRC 15959 557697RTA22200261F.j.20.1.P.Seq F M00064018C:E07 CH22PRC 15960 831361RTA22200265F.m.24.1.P.Seq F M00064569B:A09 CH22PRC 15961 194490RTA22200252F.c.10.1.P.Seq F M00063520D:D08 CH21PRN 15962 818143RTA22200254F.b.18.1.P.Seq F M00063848C:G11 CH21PRN 15963 377286RTA22200259F.a.10.1.P.Seq F M00063163A:G04 CH22PRC 15964 831361RTA22200265F.n.01.1.P.Seq F M00064569B:A09 CH22PRC 15965 385307RTA22200255F.p.07.1.P.Seq F M00064060B:D03 CH21PRN 15966 378447RTA22200251F.c.01.1.P.Seq F M00063158A:E11 CH21PRN 15967 378447RTA22200251F.b.24.1.P.Seq F M00063158A:E11 CH21PRN 15968 817514RTA22200260F.m.17.1.P.Seq F M00063968D:G08 CH22PRC 15969 818942RTA22200255F.f.03.1.P.Seq F M00063941B:C12 CH21PRN 15970 818942RTA22200267F.e.23.1.P.Seq F M00064678D:F05 CH22PRC 15971 817363RTA22200266F.f.04.1.P.Seq F M00064605C:G05 CH22PRC 15972 818942RTA22200255F.i.02.1.P.Seq F M00064025D:E07 CH21PRN 15973 818942RTA22200265F.g.23.1.P.Seq F M00064534D:F06 CH22PRC 15974 817457RTA22200267F.e.15.1.P.Seq F M00064675C:E09 CH22PRC 15975 831968RTA22200263F.f.23.1.P.Seq F M00064393B:H04 CH22PRC 15976 530941RTA22200253F.h.05.1.P.Seq F M00063785C:F03 CH21PRN 15977 763446RTA22200257F.j.05.3.P.Seq F M00064179A:C04 CH21PRN 15978 763446RTA22200255F.n.21.1.P.Seq F M00064053D:F02 CH21PRN 15979 819219RTA22200256F.f.16.1.P.Seq F M00064090C:A02 CH21PRN 15980 763446RTA22200258F.b.19.2.P.Seq F M00064248A:E02 CH21PRN 15981 10154 1598210154

TABLE 121 Nearest Nearest Neighbor Neighbor (BlastX vs. Non- (BlastN vs.Redundant SEQ Genbank) Proteins) ID ACCESSION DESCRIPTION P VALUEACCESSION DESCRIPTION P VALUE 15685 <NONE> <NONE> <NONE> 1077580hypothetical 7 protein YDR125c - yeast 15686 <NONE> <NONE> <NONE>4585925 (AC007211) 6 unknown protein 15687 <NONE> <NONE> <NONE> 1085306EVI1 protein - 4.3 human 15688 <NONE> <NONE> <NONE> 3876587 (Z81521)0.85 predicted using Genefinder; cDNA EST yk233g4.5 comes from thisgene; cDNA EST yk233g4.3 comes from this gene [Caenorhabditis elegans]15689 <NONE> <NONE> <NONE> 1086591 (U41007) 0.34 similar to S. cervisiaenuclear protein SNF2 15690 <NONE> <NONE> <NONE> 157272 (L11345) DNA-0.29 binding protein [Drosophila melanogaster] 15691 <NONE> <NONE><NONE> 2633160 (Z99108) 0.19 similar to surface adhesion YfiQ [Bacillussubtilis] 15692 <NONE> <NONE> <NONE> 755468 (U19879) 0.042 transmembraneprotein [Xenopus laevis] 15693 <NONE> <NONE> <NONE> 4507339 T brachyury0.029 (mouse) homolog protein [Homo sapiens] 15694 <NONE> <NONE> <NONE>729711 PROTEASE 0.004 DEGS PRECURSOR 3.4.21.—) hhoB - Escherichiacoli >gi|558913 (U15661) HhoB [Escherichia coli] >gi|606174 (U18997)ORF_o355 coli] >gi|1789630 (AE000402) protease [Escherichia coli] 15695<NONE> <NONE> <NONE> 3168911 (AF068718) No 8e−013 definition line found[Caenorhabditis elegans] 15696 <NONE> <NONE> <NONE> 2832777 (AL021086)/3e−040 prediction = (method:; comes from the 5′ UTR [Drosophilamelanogaster] 15697 X78712 H. sapiens 2.1 2852449 (D88207) 9.1 mRNA forprotein kinase glycerol kinase [Arabidopsis testis specific 2thaliana] >gi|2947061 (AC002521) putative protein kinase 15698 X60760 L.esculentum 2.1 157272 (L11345) DNA- 5 TDR8 mRNA binding protein[Drosophila melanogaster] 15699 U40853 Oryctolagus 2 <NONE> <NONE><NONE> cuniculus pulmonary surfactant protein B (SP-B) gene, completecds 15700 AF083655 Homo sapiens 2 <NONE> <NONE> <NONE> procollagen C-proteinase enhancer protein (PCOLCE) gene, 5′ flanking region andcomplete cds 15701 AJ223776 Staphylococcus 2 <NONE> <NONE> <NONE>warneri hld gene 15702 U40853 Oryctolagus 2 <NONE> <NONE> <NONE>cuniculus pulmonary surfactant protein B (SP-B) gene, complete cds 15703X04436 Clostridium 2 <NONE> <NONE> <NONE> tetani gene for tetanus toxin15704 Z35787 S. cerevisiae 2 157272 (L11345) DNA- 8.4 chromosome IIbinding protein reading frame [Drosophila ORF YBL026w melanogaster]15705 X78712 H. sapiens 2 2852449 (D88207) 8.2 mRNA for protein kinaseglycerol kinase [Arabidopsis testis specific 2 thaliana] >gi|2947061(AC002521) putative protein kinase 15706 Z15056 B. subtilis genes 2477124 P3A2 DNA 2.8 spoVD, murE, binding protein mraY, murD homologEWG - fruit fly (Drosophila melanogaster) 15707 S65623 cAMP-regulated 2119266 PROTEIN 0.55 enhancer- GRAINY- binding protein HEAD (DNA- 1 of 3]BINDING PROTEIN ELF- 1) (ELEMENT I-BINDING ACTIVITY) regulatory proteinelf-1 - fruit fly (Drosophila melanogaster) >gi|7939|emb |CAA33692|(X15657) Elf-1 protein (AA 1- 1063) [Drosophila melanogaster] 15708NM_004415.1 Homo sapiens 2 2649177 (AE001008) 0.2 desmoplakin conserved(DPI, DPII) hypothetical (DSP) mRNA protein mRNA, [Archaeoglobuscomplete cds fulgidus] 15709 AF031552 Vibrio cholerae 2 2088714(AF003139) 2e−013 magnesium strong similarity transporter to NADPH(mgtE) gene, oxidases; partial partial cds; CDS, the gene sensor kinasebegins in the (vieS), response neighboring regulator clone (vieA), andresponse regulator (vieB) genes, complete cds; and collagenase (vcc)gene, partial cds 15710 AF116852.1 Danio rerio 2 3800951 (AF100657) No2e−019 dickkopf-1 definition line (dkk1) mRNA, found complete cds[Caenorhabditis elegans] 15711 X82595 P. sativum fuc 1.9 <NONE> <NONE><NONE> gene 15712 AF008216 Homo sapiens 1.9 <NONE> <NONE> <NONE>candidate tumor suppressor pp32r1 15713 AF130672.1 Felis catus clone 1.9<NONE> <NONE> <NONE> Fca603 microsatellite sequence 15714 AJ007044Oryctolagus 1.9 388055 (L22981) 7.8 Cuniculus sod merozoite gene surfaceprotein- 1 [Plasmodium chabaudi] 15715 AC004497 Homo sapiens 1.9 160925(M94346) 7.7 chromosome 21, A.1.12/9 P1 clone antigen LBNL#6[Schistosoma mansoni] 15716 U30290 Rattus 1.9 3024079 GALECTIN-4 4.5norvegicus (LACTOSE- galanin receptor BINDING GALR1 mRNA, LECTIN 4) (L-complete cds 36 LACTOSE BINDING PROTEIN) (L36LBP) >gi|2281707sapiens] >gi|2623387 (U82953) galectin-4 [Homo sapiens] 15717 Y13234Chironomus 1.9 4567068 (AF125568) 3.4 tentans mRNA tumor for chitinase,suppressing STF 1695 bp cDNA 4 [Homo sapiens] 15718 NM_003644.1 Homosapiens 1.9 125560 PROTEIN 0.53 growth arrest- KINASE C, specific 7GAMMA TYPE (GAS7) mRNA C (EC 2.7.1.—) > :: gamma - rabbitemb|AJ224876| >gi|165652 HSAJ4876 (M19338) Homo sapience protein kinasemRNA for delta GAS7 protein [Oryctolagus cuniculus] 15719 AB013448.1Oryza sativa 1.8 <NONE> <NONE> <NONE> gene for Pib, complete cds 15720D63854 Human 1.8 <NONE> <NONE> <NONE> cytomegalovirus DNA, replicationorigin 15721 AB002340 Human mRNA 1.8 <NONE> <NONE> <NONE> for KIAA0342gene, complete cds 15722 AF017779 Mus musculus 1.8 <NONE> <NONE> <NONE>vitamin D receptor gene, promoter region 15723 D63854 Human 1.8 <NONE><NONE> <NONE> cytomegalovirus DNA, replication origin 15724 M24102Bovine 1.8 <NONE> <NONE> <NONE> ADP/ATP translocase T1 mRNA, completecds. 15725 AC004497 Homo sapiens 1.8 <NONE> <NONE> <NONE> chromosome 21,P1 clone LBNL#6 15726 M37394 Rat epidermal 1.8 <NONE> <NONE> <NONE>growth factor receptor mRNA. 15727 AF006304 Saccharomyces 1.8 <NONE><NONE> <NONE> cerevisiae protein tyrosine phosphatase (PTP3) gene,complete cds 15728 D13454 Candida 1.8 <NONE> <NONE> <NONE> albicansCACHS3 gene for chitin synthase III 15729 Y00354 Xenopus laevis 1.81077580 hypothetical 7.5 gene encoding protein vitellogenin A2 YDR125c -yeast 15730 U90936 Aspergillus 1.8 4337033 (AF124138) 7.3 niger px27transcriptional gene, promoter activator protein region CdaR[Streptomyces coelicolor] transcriptional regulator [Streptomycescoelicolor] 15731 D84448 Cavia cobaya 1.8 4704603 (AF109916) 7.1 mRNAfor putative Na+, K+- dehydrin ATPase beta-3 subunit, complete cds 15732AF039948 Xenopus laevis 1.8 1695839 (U58151) 5.6 clone H-0 envelopetranscription glycoprotein elongation factor [Human S-II (TFIIS)immunodeficiency precursor RNA, virus type 1] isoform TFIIS.h, partialcds 15733 M18061 Xenopus laevis 1.8 780502 (U18466) AP 3.1 vitellogininendonuclease gene, complete class II [African cds. swine fevervirus] >gi|10975251|prf ||2113434ET AP endonuclease: ISO TYPE = class II[African swine fever virus] 15734 U61112 Mus musculus 1.8 3043646(AB011133) 1.9 Eya3 homolog KIAA0561 mRNA, protein [Homo complete cdssapiens] 15735 AB018442 Oryza sativa 1.8 4455041 (AF116463) 0.49 mRNAfor unknown phytochrome C, [Streptomyces complete cds lincolnensis]15736 D63854 Human 1.8 1169200 DNA- 0.22 cytomegalovirus DAMAGE- DNA,replication REPAIR/TOLERATION origin PROTEIN DRT111PRECURSOR >gi|421829|pir ||S33706 DNA-damage resistance protein -Arabidopsis thaliana and DNA-damage resistance protein (DRT111) mRNA,complete cds.], gene product [Arabidopsis thaliana] 15737 D26549 BovinemRNA 1.8 755468 (U19879) 0.042 for adseverin, transmembrane complete cdsprotein [Xenopus laevis] 15738 J05211 Human 1.8 728867 ANTER- 0.015desmoplakin SPECIFIC mRNA, 3′ end. PROLINE- RICH PROTEIN APGPRECURSOR >gi|99694|pir ||S21961 proline-rich protein APG - Arabidopsisthaliana >gi|22599|emb |CAA42925| 15739 NM_004415.1 Homo sapiens 1.8728867 ANTER- 0.015 desmoplakin SPECIFIC (DPI, DPII) PROLINE- (DSP) mRNARICH mRNA, PROTEIN APG complete cds PRECURSOR >gi|99694|pir ||S21961proline-rich protein APG - Arabidopsis thaliana >gi|22599|emb |CAA42925|15740 AF038604 Caenorhabditis 1.8 3877951 (Z81555) 3e−008 elegans cosmidpredicted using B0546 Genefinder 15741 AF038604 Caenorhabditis 1.83877951 (Z81555) 2e−011 elegans cosmid predicted using B0546 Genefinder15742 U23551 Prochlorothrix 1.8 2828280 (AL021687) 2e−013 hollandicaputative protein phosphomannomutase [Arabidopsisthaliana] >gi|2832633|emb |CAA16762 |(AL021711) putative protein[Arabidopsis thaliana] 15743 S60150 ORF1. . . ORF6 1.8 1065454 (U40410)2e−019 {3′ terminal C54G7.2 gene reigon} product [chrysanthemum[Caenorhabditis virus B CVB, elegans] Genomic RNA, 6 genes, 3426 nt]15744 AB014558 Homo sapiens 1.8 3850072 (AL033385) 6e−027 mRNA fordna-directed rna KIAA0658 polymerase iii protein, partial subunit cds[Schizosaccharo myces pombe] 15745 X17191 E. gracilis 1.7 <NONE> <NONE><NONE> chloroplast RNA polymerase rpoB-rpoC1- rpoC2 operon 15746 X07729R. norvegicus 1.7 4584544 (AL049608) 8.8 gene encoding extensin-likeneuron-specific protein enolase, exons 8-12 15747 D38178 Human gene for1.7 73714 infected cell 1.1 cytosolic protein ICP34.5 - phospholipasehuman A2, exon 1 herpesvirus 1 (strain F) >gi|330123 (M12240) infectedcell protein [Herpes simplex virus type 1] 15748 U23551 Prochlorothrix1.7 2828280 (AL021687) 2e−010 hollandica putative proteinphosphomannomutase [Arabidopsis thaliana] >gi|2832633|emb |CAA16762|(AL021711) putative protein [Arabidopsis thaliana] 15749 Y00525Klebsiella 1.6 3800951 (AF100657) No 6e−013 pneumoniae definition linenifL gene for found regulatory [Caenorhabditis protein elegans] 15750AF100170.1 Bos taurus 1.5 463552 (U05877) AF-1 0.074 major fibrous [Homosapiens] sheath protein precursor, mRNA, complete cds 15751 Y13441 Homosapiens 0.74 <NONE> <NONE> <NONE> Rox gene, exon 2 15752 L46792Actinidia 0.73 3170252 (AF043636) 0.001 deliciosa clone circumsporozoiteAdXET-5 protein xyloglucan [Plasmodium endotransglycosylase chabaudi]precursor (XET) mRNA, complete cds 15753 U73489 Drosophila 0.7 3915994HYPOTHETICAL 3e−005 melanogaster 53.2 KD Nem (nem) PROTEIN IN mRNA,PRC-PRPA complete cds INTERGENIC REGION 15754 U95097 Xenopus laevis 0.68157272 (L11345) DNA- 8.5 mitotic binding protein phosphoprotein[Drosophila 43 mRNA, melanogaster] partial cds 15755 AF082012Caenorhabditis 0.67 2494313 PUTATIVE 8.4 elegans UDP-N- TRANSLATIONacetylglucosamine: INITIATION a-3-D- FACTOR EIF- mannoside b- 2B SUBUNIT1 1,2-N- (EIF-2B GDP- acetylglucosaminyltransferase I GTP (gly-14) mRNA,EXCHANGE complete cds FACTOR) eIF- 2B, subunit alpha- Methanococcusjannaschii aIF- 2B, subunit delta (aIF2BD) [Methanococcus jannaschii]15756 U04354 Mus musculus 0.67 4755188 (AC007018) 8e−026 ADSEVERINunknown protein mRNA, complete cds 15757 M68881 S. pombe cigl+ 0.672078441 (U56964) weak 2e−030 gene, complete similarity to S. cerevisiaecds. intracellular protein transport protein US)1 (SP: P25386) 15758U95097 Xenopus laevis 0.66 2829685 PROTEIN- 6.2 mitotic TYROSINEphosphoprotein PHOSPHATASE X 43 mRNA, PRECURSOR partial cds (R-PTP-X)(PTP IA- 2BETA) (PROTEIN TYROSINE PHOSPHATASE- NP) (PTP- NP) >gi|1515425(U57345) protein tyrosine phosphatase-NP [Mus musculus] 15759 Z15056 B.subtilis genes 0.66 477124 P3A2 DNA 2.1 spoVD, murE, binding proteinmraY, murD homolog EWG - fruit fly (Drosophila melanogaster) 15760M86808 Human pyruvate 0.65 <NONE> <NONE> <NONE> dehydrogenase complex(PDHA2) gene, complete cds. 15761 J03754 Rat plasma 0.65 4507549transmembrane 8e−006 membrane protein with Ca2+ ATPase- EGF-like andisoform 2 two follistatin- mRNA, like domains 1 complete cds. >gi|75546615762 NM_000887.1 Homo sapiens 0.64 <NONE> <NONE> <NONE> integrin, alphaX (antigen CD11C emb|Y00093|HSP15095 H. sapiens mRNA for leukocyteadhesion glycoprotein p150, 95 15763 L27080 Human 0.64 <NONE> <NONE><NONE> melanocortin 5 receptor (MC5R) gene, complete cds. 15764 U07890Mus musculus 0.64 <NONE> <NONE> <NONE> C57BL/6J epidermal surfaceantigen (mesa) mRNA, complete cds. 15765 AF079139 Streptomyces 0.643041869 (U96109) 2.8 venezuelae proline-rich pikCD operon, transcriptioncomplete factor ALX3 sequence [Mus musculus] 15766 M16140 Chicken 0.64123984 ACROSIN 4e−008 ovoinhibitor INHIBITORS gene, exon 15. IIA AND IIB15767 NM_000887.1 Homo sapiens 0.63 <NONE> <NONE> <NONE> integrin, alphaX (antigen CD11C emb|Y00093|HSP15095 H. sapiens mRNA for leukocyteadhesion glycoprotein p150, 95 15768 Z17316 Kluyveromyces 0.63 <NONE><NONE> <NONE> lactis for gene encoding phosphofructokinase beta subunit15769 Z25470 H. sapiens 0.63 <NONE> <NONE> <NONE> melanocortin 5receptor gene, complete CDS 15770 L19954 Bacillus subtilis 0.63 <NONE><NONE> <NONE> feuA, B, and C genes, 3 ORFs, 2 complete cds's and 5'end.15771 U44405 Spiroplasma 0.63 2499642 SERINE/THREONINE- 7.7 citriPROTEIN chromosome KINASE STE20 pre-inversion HOMOLOG border,SPV1- >gi|1737181 like sequences, (U73457) transposase Cst20p [Candidagene, partial albicans] cds, adhesin-like protein P58 gene, completecds. 15772 Z28264 S. cerevisiae 0.63 3880930 (AL021481) 2e−014chromosome XI similar to reading frame Phosphoglucomutase ORF YKR039wand phosphomannomutase phosphoserine; cDNA EST EMBL: D36168 comes fromthis gene; cDNA EST EMBL: D70697 comes from this gene; cDNA ESTyk373h9.5 comes from this gene; cDNA EST EMBL: T00805 . . . 15773AE001107 Archaeoglobus 0.62 <NONE> <NONE> <NONE> fulgidus section 172 of172 of the complete genome 15774 Z14112 B. firmus TopA 0.62 310115(L02530) 0.026 gene encoding Drosophila DNA polarity gene topoisomeraseI (frizzled) homologue 15775 AF118101 Toxoplasma 0.62 726403 (U23175)4e−018 gondii protein similar to anion kinase 6 (tpk6) exchange mRNA,protein complete cds [Caenorhabditis elegans] 15776 M59743 Rabbitcardiac 0.61 <NONE> <NONE> <NONE> muscle Ca-2+ release channel 15777M12036 Human tyrosine 0.61 61962 (X58484) gag 7.5 kinase-type [Simianfoamy receptor (HER2) virus] gene, partial cds. 15778 AF043195 Homosapiens 0.61 1572629 (U69699) 7.5 tight junction unknown protein proteinZO (ZO- precursor [Mus 2) gene, musculus] alternative splice products,promoter and exon A 15779 U18178 Human HLA 0.61 1336688 (S81116) 5.7class I genomic properdin survey [guinea pigs, sequence. spleen,Peptide, 470 aa] [Cavia] 15780 U44405 Spiroplasma 0.61 2827531(AL021633) 3.3 citri hypothetical chromosome protein pre-inversionborder, SPV1- like sequences, transposase gene, partial cds,adhesin-like protein P58 gene, complete cds. 15781 Z33011 M. capricolum0.61 3915729 HYPERPLASTIC 0.26 DNA for DISCS CONTIG PROTEIN MC008 (HYDPROTEIN) >gi|2673887 (L14644) hyperplastic discs protein 15782NM_001429.1 Homo sapiens 0.61 4204294 (AC003027) 5e−005 E1A bindinglcl|prt_seq No protein p300 definition line mRNA, found complete cds. >:: gb|I62297|I62297 Sequence 1 from patent US 5658784 15783 Z25418 C.familiaris 0.61 3877493 (Z48583) 1e−007 MHC class Ib similar to gene(DLA-79) ATPases gene, complete associated with CDS various cellularactivities (AAA); cDNA EST EMBL: Z14623 comes from this gene; cDNA ESTEMBL: D75090 comes from this gene; cDNA EST EMBL: D72255 comes from thisgene; cDNA EST yk200e4.5 . . . 15784 AB002150 Bacillus subtilis 0.6<NONE> <NONE> <NONE> DNA for FeuB, FeuA, YbbB, YbbC, YbbD, YbzA, YbbE,YbbF, YbbH, YbbI, YbbJ, YbbK, YbbL, YbbM, YbbP, complete cds 15785Y07786 V. cholerae 0.6 <NONE> <NONE> <NONE> ORF's involved inlipopolysaccharide synthese 15786 Z17316 Kluyveromyces 0.6 <NONE> <NONE><NONE> lactis for gene encoding phosphofructokinase beta subunit 15787Z71403 S. cerevisiae 0.6 <NONE> <NONE> <NONE> chromosome XIV readingframe ORF YNL127w 15788 L34641 Homo sapiens 0.6 1147634 (U42213) 9.6platelet/endothelial micronemal cell adhesion TRAP-C1 molecule-1 proteinhomolog (PECAM-1) gene, exon 10. 15789 AF070572 Homo sapiens 0.6 399034N- 2.5 clone 24778 ACETYLMUR unknown AMOYL-L- mRNA ALANINE AMIDASE AMIBPRECURSOR >gi|628763|pir ||S41741 N- acetylmuramoyl- L-alanine amidase(EC 3.5.1.28) - Escherichia coli >gi|304914 (L19346) N- acetylmuramoyl-L-alanine amidase [Escherichia coli] N- acetylmuramoyl- l-alanineamidase II; a 15790 X75627 C. burnetii trxB, 0.6 3036833 (AJ003163) 0.28spoIIIE and serS apsB genes [Emericella nidulans] 15791 Z99765 FlaveriapringleigdcsH 0.59 <NONE> <NONE> <NONE> gene 15792 U02538 Mycoplasma0.59 <NONE> <NONE> <NONE> hyopneumoniae J ATCC 25934 23S rRNA gene,partial sequence 15793 Z71403 S. cerevisiae 0.59 <NONE> <NONE> <NONE>chromosome XIV reading frame ORF YNL127w 15794 X03942 Mouse simple 0.59<NONE> <NONE> <NONE> repetitive DNA (sqr family) transcript (clone pmlc2) with conserved GACA/GATA repeats 15795 U11844 Mus musculus 0.59<NONE> <NONE> <NONE> glucose transporter (GLUT3) gene, exon 1 15796D63395 Homo sapiens 0.59 4433616 (AF107018) 1.8 mRNA for alpha- NOTCH4,mannosidase IIx partial cds [Mus musculus] 15797 Z33011 M. capricolum0.59 3915729 HYPERPLASTIC 0.27 DNA for DISCS CONTIG PROTEIN MC008 (HYDPROTEIN) >gi|2673887 (L14644) hyperplastic discs protein 15798 U05670Haemophilus 0.58 <NONE> <NONE> <NONE> influenzae DL42 Lex2A and Lex2Bgenes, complete cds. 15799 L27080 Human 0.58 123984 ACROSIN 2e−006melanocortin 5 INHIBITORS receptor IIA AND IIB (MC5R) gene, completecds. 15800 AF043195 Homo sapiens 0.57 1572629 (U69699) 6.7 tightjunction unknown protein protein ZO (ZO- precursor [Mus 2) gene,musculus] alternative splice products, promoter and exon A 15801 U57707Bos taurus 0.57 807646 (M17294) 0.068 activin receptor unknown proteintype IIB [Human precursor herpesvirus 4] 15802 Z17316 Kluyveromyces 0.56<NONE> <NONE> <NONE> lactis for gene encoding phosphofructokinase betasubunit 15803 M21535 Human erg 0.56 <NONE> <NONE> <NONE> protein (ets-related gene) mRNA, complete cds. 15804 M64932 Candida maltosa 0.563219524 (AF069428) 1.3 cyclohexamide NADH resistance dehydrogenaseprotein subunit IV [Alligator mississippiensis] >gi|3367630|emb|CAA73570| (Y13113) NADH dehydrogenase subunit 4 [Alligatormississippiensis] 15805 AE000342 Escherichia coli 0.56 3874685 (Z78539)0.088 K-12 MG1655 Similarity to section 232 of S. pombe 400 of thehypothetical complete protein genome C4G8.04 (SW: YAD4_SC HPO); cDNA ESTEMBL: D27846 comes from this gene; cDNA EST EMBL: D27845 comes from thisgene; cDNA EST yk202h7.3 comes from this gene; cDNA EST yk202h7.5 come .. . 15806 Z15056 B. subtilis genes 0.55 477124 P3A2 DNA 3.7 spoVD, murE,binding protein mraY, murD homolog EWG - fruit fly (Drosophilamelanogaster) 15807 Z58167 H. sapiens CpG 0.53 <NONE> <NONE> <NONE>island DNA genomic Mse1 fragment, clone 30e10, forward readcpg30e10.ft1b 15808 M27159 Rat potassium 0.53 1850920 (U21247) Bet 0.9channel-Kv2 [Human gene, partial spumaretrovirus] cds. 15809 M15555Mouse Ig 0.24 <NONE> <NONE> <NONE> germline V- kappa-24 chain (VK24C)gene, exons 1 and 2. 15810 U95097 Xenopus laevis 0.24 399109TRANSCRIPTION 4 mitotic FACTOR phosphoprotein BF-1 (BRAIN 43 mRNA,FACTOR 1) partial cds (BF1) >gi|92020|pir ||JH0672 brain factor 1protein - rat >gi|203135 (M87634) BF-1 [Rattus norvegicus] 15811AJ002014 Crythecodinium 0.24 416704 BALBIANI 0.36 cohnii mRNA RING fornuclear PROTEIN 3 protein JUS1 PRECURSOR balbiani ring 3 (BR3)[Chironomus tentans] 15812 L35330 Rattus 0.23 1388158 (U58204) 8.8norvegicus myomesin glutathione S- [Gallus gallus] transferase Yb3subunit gene, complete cds. 15813 NM_001432.1 Homo sapiens 0.23 2851520TRANSFORMING 2e−008 epiregulin GROWTH (EREG) mRNA FACTOR > :: ALPHAdbj|D30783|D3 PRECURSOR 0783 Homo (TGF-ALPHA) sapiens mRNA (EGF-LIKE forepiregulin, TGF) (ETGF) complete cds (TGF TYPE 1) precursor -rat >gi|207282 (M31076) transforming growth factor alpha precursor[Rattus norvegicus] 15814 U57043 Cebus apella 0.22 <NONE> <NONE> <NONE>gamma globin (gamma 1) gene, complete cds 15815 AB023188.1 Homo sapiens0.22 <NONE> <NONE> <NONE> mRNA for KIAA0971 protein, complete cds 15816M18105 Yeast 0.22 <NONE> <NONE> <NONE> (S. cerevisiae) SST2 geneencoding desensitization to alpha- factor pheromone, complete cds. 15817AJ001113 Homo sapiens 0.22 3122961 ENHANCER 8.5 UBE3A gene, OF SPLITexon 16 GROUCHO- LIKE PROTEIN 1 >gi|2408145 (U18775) enhancer of splitgroucho 15818 L35330 Rattus 0.22 1388158 (U58204) 8.1 norvegicusmyomesin glutathione S- [Gallus gallus] transferase Yb3 subunit gene,complete cds. 15819 D42042 Human mRNA 0.22 4827063 zinc finger 6.1 forKIAA0085 protein 142 gene, partial cds (clone pHZ-49) >gi|3123312|sp|P52746|Z142_(—) HUMAN ZINC FINGER PROTEIN 142 (KIAA0236)(HA4654) >gi|1510147|d bj|BAA13242| 15820 L35330 Rattus 0.22 2853301(AF007194) 1.6 norvegicus mucin [Homo glutathione S- sapiens]transferase Yb3 subunit gene, complete cds. 15821 Z11653 H. sapiens DBH0.22 3819705 (AL032824) 1.2 gene complex syntaxin binding repeat protein1; sec1 polymorphism family secretory DNA. protein [Schizosaccharo mycespombe] 15822 L29063 Candida 0.22 3046871 (AB003753) 0.32 albicans fattyhigh sulfur acid synthase protein B2E alpha subunit [Rattus (FAS2) gene,norvegicus] complete cds. 15823 M64865 Horse alcohol 0.22 2213909(AF004874) 0.037 dehydrogenase- latent TGF-beta S-isoenzyme bindingprotein- mRNA, 2 [Mus complete cds. musculus] 15824 Y09472 B. taurusgene 0.21 2909874 (AF047829) 7.6 encoding melatonin- preprododecaperelated receptor ptide [Ovis aries] 15825 Y09472 B. taurus gene 0.212909874 (AF047829) 7.5 encoding melatonin- preprododecape relatedreceptor ptide [Ovis aries] 15826 X80301 N. tabacum axi 1 0.21 2832715(AJ003066) 6 gene subunit beta of the mitochondrial fatty acid beta-oxydation multienzyme complex [Bos taurus] 15827 AF073485 Homo sapiens0.21 2224559 (AB002307) 3.3 MHC class I- KIAA0309 related protein [Homosapiens] MR1 precursor (MR1) gene, partial cds 15828 S78251 growthhormone 0.21 729381 DYNAMIN-1 2 receptor (DYNAMIN {alternativelyBREDNM19) spliced, exon 1B} [sheep, Merino, skeletal muscle, mRNAPartial, 438 nt] 15829 U16135 Synechococcus 0.21 135514 T-CELL 0.02 sp.Clp protease RECEPTOR proteolytic BETA CHAIN subunit PRECURSOR precursor(ANA 11) - rabbit 15830 X95601 M. hominis lmp3 0.21 2995445 (Y10496)CDV- 0.005 and lmp4 genes 1 protein [Mus musculus] 15831 X95601 M.hominis lmp3 0.21 2995447 (Y10495) CDV- 0.005 and lmp4 genes 1R protein[Mus musculus] 15832 AF124249.1 Homo sapiens 0.21 423456 epidermal8e−010 SH2-containing growth factor- protein Nsp1 receptor-binding mRNA,protein GRB-4 - complete cds mouse (fragment) 15833 AF030282 Danio rerio0.21 3928083 (AC005770) 2e−014 homeobox unknown protein protein Six7[Arabidopsis (six7) mRNA, thaliana] complete cds 15834 X83427 O.anatinus 0.21 132575 RIBONUCLEASE 3e−021 mitochondrial INHIBITOR DNA,complete genome 15835 AJ001113 Homo sapiens 0.2 <NONE> <NONE> <NONE>UBE3A gene, exon 16 15836 AF081533.1 Anopheles 0.2 <NONE> <NONE> <NONE>gambiae putative gram negative bacteria binding protein gene, completecds 15837 U70316 Dictyostelium 0.2 <NONE> <NONE> <NONE> discoideum IonA(iona) gene, partial cds 15838 AF009341 Homo sapiens 0.2 <NONE> <NONE><NONE> E6-AP ubiquitin-protein ligase 15839 L35330 Rattus 0.2 3702275(AC005793) 2.5 norvegicus KIAA0561 glutathione S- protein [AA 1-593]transferase Yb3 [Homo subunit gene, sapiens] complete cds. 15840AE000573.1 Helicobacter 0.2 3947855 (AL034381) 2.5 pylori 26695 putativeGolgi section 51 of membrane 134 of the protein complete genome 15841X83230 G. gallus 0.2 3258596 (U95821) 0.81 hsp90beta gene putativetransmembrane GTPase [Drosophila melanogaster] 15842 X57157 Chicken mRNA0.2 108325 insulin-like 0.17 for Hsp47, heat growth factor- shockprotein 47 binding protein 6 15843 M58748 Chicken alpha- 0.2 1086863(U41272) 4e−005 globin gene T03G11.6 gene domain with product structuralmatrix [Caenorhabditis attachment sites. elegans] 15844 AB016815Anthocidaris 0.2 423456 epidermal 1e−012 crassispina growth factor- mRNAfor Src- receptor-binding type protein protein GRB-4 - tyrosine kinase,mouse complete cds (fragment) 15845 AF030282 Danio rerio 0.2 3928083(AC005770) 3e−014 homeobox unknown protein protein Six7 [Arabidopsis(six7) mRNA, thaliana] complete cds 15846 AL035559 Streptomyces 0.22088714 (AF003139) 3e−022 coelicolor strong similarity cosmid 9F2 toNADPH oxidases; partial CDS, the gene begins in the neighboring clone15847 S79641 SDH = succinate 0.2 4755188 (AC007018) 2e−022 dehydrogenaseunknown protein flavoprotein subunit Mutant, 387 nt] 15848 X75383 H.sapiens 0.19 <NONE> <NONE> <NONE> mRNA for TFIIA-alpha 15849 U53901Hippopotamus 0.19 <NONE> <NONE> <NONE> amphibius b- casein gene, exon 7,partial cds 15850 J05265 Mouse 0.19 77356 hypothetical 0.0005 interferon70K protein - gamma receptor eggplant mosaic mRNA, virus complete cds.15851 U72353 Rattus 0.19 3880857 (AL031633) 2e−006 norvegicus cDNA ESTlamin B1 yk404d1.5 mRNA, comes from this complete cds gene; cDNA ESTyk404d1.3 comes from this gene 15852 AB016815 Anthocidaris 0.19 3930217(AF047487) 2e−007 crassispina Nck-2 [Homo mRNA for Src- sapiens] typeprotein tyrosine kinase, complete cds 15853 D10911 Mus musculus 0.192662366 (D86332) 5e−011 DNA for MS2 membrane type- protein, 2 matrixcomplete cds metalloproteinase [Mus musculus] 15854 AB015345 Homosapiens 0.075 3877417 (Z66564) 6.4 HRIHFB2216 similar to anion mRNA,partial exchange cds protein 15855 AF086410 Homo sapiens 0.075 3023371PHEROMONE 4.9 full length insert B BETA 1 cDNA clone RECEPTOR ZD77B0315856 K02024 Human T-cell 0.075 2791527 (AL021246) 0.11 lymphotropicPE_PGRS virue type II env [Mycobacterium gene encoding tuberculosis]envelope glycoprotein, complete cds. 15857 M10188 X. laevis 0.0744753163 huntingtin 2.8 mitochondrial DISEASE DNA containing PROTEIN) (HDthe D-loop, and PROTEIN) the 12S rRNA, >gi|454415 apocytochrome (L12392)b, Glu-tRNA, Huntington's Thr-tRNA, Pro- Disease protein tRNA and Phe-[Homo sapiens] tRNA genes. 15858 X85525 G. gallus AG 0.073 984339(U20966) Rev 3.6 repeat region [Simian (GgaMU130) immunodeficiencyvirus] 15859 AJ238394.1 Homo sapiens 0.07 4240219 (AB020672) 2 AML2 geneKIAA0865 (partial) protein [Homo sapiens] 15860 AF039704 Homo sapiens0.069 2894106 (Z78279) 0.39 lysosomal Collagen alpha1 pepstatin [Rattusinsensitive norvegicus] protease (CLN2) gene, complete cds 15861 K02024Human T-cell 0.068 4504857 potassium 0.5 lymphotropic intermediate/smallvirue type II env conductance gene encoding calcium- envelope activatedglycoprotein, channel, complete cds. subfamily N, member 3 >gi|3309531(AF031815) calcium- activated potassium channel [Homo sapiens] 15862Z60719 H. sapiens CpG 0.068 4826874 nucleoporin 0.044 island DNA 214 kD(CAIN) genomic Mse1 PROTEIN fragment, clone NUP214 33a11, forward(NUCLEOPORIN read NUP214) cpg33a11.ft1m (214 KD NUCLEOPORIN)transforming protein (can) - human sapiens] 15863 AF053994 Lycopersicon0.068 2842699 PUTATIVE 9e−009 esculentum UBIQUITIN Hcr2-0A (Hcr2-CARBOXYL- 0A) gene, TERMINAL complete cds HYDROLASE C6G9.08 (UBIQUITINTHIOLESTERASE) (UBIQUITIN- SPECIFIC PROCESSING PROTEASE) 15864AJ233650.1 Equus caballus 0.067 <NONE> <NONE> <NONE> endogenousretroviral sequence ERV- L pol gene, clone ERV-L Horse1 15865 M10188 X.laevis 0.067 4753163 huntingtin 2.5 mitochondrial DISEASE DNA containingPROTEIN) (HD the D-loop, and PROTEIN) the 12S rRNA, >gi|454415apocytochrome (L12392) b, Glu-tRNA, Huntington's Thr-tRNA, Pro- Diseaseprotein tRNA and Phe- [Homo sapiens] tRNA genes. 15866 U14646 Murinehepatitis 0.067 3880930 (AL021481) 1e−019 virus Y strain S similar toglycoprotein Phosphoglucomutase gene, complete and cds.phosphomannomutase phosphoserine; cDNA EST EMBL: D36168 comes from thisgene; cDNA EST EMBL: D70697 comes from this gene; cDNA EST yk373h9.5comes from this gene; cDNA EST EMBL: T00805 . . . 15867 X15373 Mouse0.066 164507 (M81771) 9.4 cerebellum immunoglobulin mRNA for P400gamma-chain protein [Sus scrofa] 15868 AF086410 Homo sapiens 0.0663023371 PHEROMONE 4.2 full length insert B BETA 1 cDNA clone RECEPTORZD77B03 15869 AL034492 Streptomyces 0.066 3800951 (AF100657) No 3e−015coelicolor definition line cosmid 6C5 found [Caenorhabditis elegans]15870 L13377 Staphylococcus 0.065 <NONE> <NONE> <NONE> aureusenterotoxin gene, 3′ end. 15871 U83478 Thelephoraceae 0.065 3877335(Z92786) 9.1 sp. ‘Taylor #13’ predicted using ITS1, 5.8S Genefinderribosomal RNA gene, and ITS2, complete sequence 15872 AJ002014Crythecodinium 0.065 1213283 (U40576) SIM2 0.47 cohnii mRNA [Musmusculus] for nuclear protein JUS1 15873 AB016804 Aloe 0.065 2832777(AL021086)/ 5e−036 arborescens prediction = (method:; mRNA for comesNADP-malic from the 5′ enzyme, UTR complete cds [Drosophilamelanogaster] 15874 AJ002014 Crythecodinium 0.063 1213283 (U40576) SIM20.45 cohnii mRNA [Mus musculus] for nuclear protein JUS1 15875AB023143.1 Homo sapiens 0.024 132575 RIBONUCLEASE 8e−026 mRNA forINHIBITOR KIAA0926 protein, complete cds 15876 U72966 Human 0.022 <NONE><NONE> <NONE> hepatocyte nuclear factor 4- alpha gene, exon 7 15877X02801 Mouse gene for 0.022 2231607 (U85917) nef 7 glial fibrillaryprotein [Human acidic protein immunodeficiency virus type 1] 15878AF017636 Mesocricetus 0.022 2723362 (AF023459) 0.097 auratus 3-keto-lustrin A steroid reductase [Haliotis rufescens] 15879 Z36879 F.pringlei 0.008 <NONE> <NONE> <NONE> gdcsPA gene for P-protein of theglycine cleavage system 15880 X73150 P. sativum 0.008 1572629 (U69699)8.6 GapC1 gene unknown protein precursor [Mus musculus] 15881 AJ239031.1Homo sapiens 0.008 4508019 zinc finger 0.01 LSS gene, protein 231partial, exons protein [Homo 22, 23 and sapiens] joined CDS 15882 U76602Human 180 kDa 0.007 3170252 (AF043636) 0.0001 bullous circumsporozoitepemphigoid protein antigen 2/type [Plasmodium XVII collagen chabaudi](BPAG2/COL17A1) gene, exons 49, 50, 51 and 52 15883 M11283 Aplysia 0.0073874685 (Z78539) 9e−013 californica Similarity to FMRFamide S. pombemRNA, partial hypothetical cds, clone protein FMRF-2. C4G8.04 (SW:YAD4_SCHPO); cDNA EST EMBL: D27846 comes from this gene; cDNA EST EMBL:D27845 comes from this gene; cDNA EST yk202h7.3 comes from this gene;cDNA EST yk202h7.5 come . . . 15884 J03998 P. falciparum 0.003 <NONE><NONE> <NONE> glutamic acid- rich protein gnen, complete cds. 15885Z23143 M. musculus 0.002 2393890 (AF006064) 1e−011 ALK-6 mRNA, proteinkinase complete CDS homolog [Fowlpox virus] 15886 AB007914 Homo sapiens0.001 2136964 cysteine-rich 1.9 mRNA for hair keratin KIAA0445associated protein, protein - rabbit complete cds >gi|510541|emb|CAA56339| (X80035) cysteine rich hair keratin associated protein 15887AB012105 Brassica rapa 0.0008 3687246 (AC005169) 5.5 mRNA for putativeSLG45, suppressor complete cds protein [Arabidopsis thaliana] 15888L41608 Methylobacterium 0.0008 3024235 NERVOUS- 5.1 extorquens SYSTEM(clone pDN9, SPECIFIC HINDIIIAB) OCTAMER- mxaS gene 3′ BINDING end,mxaA, TRANSCRIPTION mxaC, mxaK, FACTOR mxaL and mxaD N-OCT 3 genes,complete PROTEIN) cds. 15889 AB007914 Homo sapiens 0.0008 2136964cysteine-rich 2.5 mRNA for hair keratin KIAA0445 associated protein,protein - rabbit complete cds >gi|510541|emb |CAA56339| (X80035)cysteine rich hair keratin associated protein 15890 AC002293 Genomic0.0008 2789557 (AF034316) 0.0002 sequence from MHC class I Human 9q34,antigen [Triakis complete scyllium] sequence [Homo scyllium] sapiens]15891 L16013 Rattus 9e−005 <NONE> <NONE> <NONE> norvegicus Q- like genesequence 15892 AF148512.1 Homo sapiens 9e−005 <NONE> <NONE> <NONE>hexokinase II gene, promoter region 15893 U94776 Human muscle 9e−0054759138 solute carrier 5.4 glycogen family 7 phosphorylase transporter 3(PYGM) gene, [Homo sapiens] exons 6 through 17 15894 X56030 H. sapiensIAPP 1e−005 <NONE> <NONE> <NONE> gene for amyloid polypeptide, exon 115895 U36515 Human CT 4e−007 2435616 (AF026215) No 0.85 microsatellite,definition line clone GM5927- found CT-2-3, from [Caenorhabditis thetandemly elegans] repeated genes encoding U2 small nuclear RNA (RNU2locus) 15896 AB011119 Homo sapiens 4e−007 4758508 airway trypsin- 3e−031mRNA for like protease KIAA0547 protease [Homo protein, sapiens]complete cds 15897 NM_000521.1 Homo sapiens 5e−008 2119379 slow muscle2.8 hexosaminidase troponin T - B (beta chicken T polypeptide) [Gallusgallus] (HEXB) mRNA 15898 X13895 Human serum 4e−008 699405 (U18682)novel 7.7 amyloid A antigen receptor (GSAA1) gene, [Ginglymostomacomplete cds cirratum] 15899 AB009288.1 Homo sapiens 4e−008 4520342(AB008893) N- 3e−006 mRNA for N- copine [Mus copine, musculus] completecds 15900 AB011119 Homo sapiens 4e−008 4758508 airway trypsin- 1e−028mRNA for like protease KIAA0547 protease [Homo protein, sapiens]complete cds 15901 X13895 Human serum 5e−009 699405 (U18682) novel 7.8amyloid A antigen receptor (GSAA1) gene, [Ginglymostoma complete cdscirratum] 15902 X13895 Human serum 2e−009 699405 (U18682) novel 7.2amyloid A antigen receptor (GSAA1) gene, [Ginglymostoma complete cdscirratum] 15903 U64997 Bos taurus 2e−009 3914810 RIBONUCLEASE 3e−018ribonuclease K6 K6 gene, partial cds PRECURSOR (RNASE K6) >gi|2745760(AF037086) ribonuclease k6 precursor 15904 J02635 Rat liver alpha-2e−009 112913 ALPHA-2- 4e−019 2-macroglobulin MACROGLOBULIN mRNA,PRECURSOR complete cds. precursor - rat >gi|202592 (J02635) prealpha-2-macroglobulin [Rattus norvegicus] 15905 Z78141 M. musculus 5e−0103219569 (AL023893)/ 4e−009 partial cochlear prediction = (method:; mRNA(clone 29C9) 15906 AF060917 Gambusia 2e−010 3874618 (Z48241) 0.096affinis similar to coiled microsatellite coil domains; Gafu6 cDNA ESTyk302g12.5 comes from this gene; cDNA EST yk365d10.5 comes from thisgene; cDNA EST yk461c1.5 comes from this gene [Caenorhabditis elegans]coil domains; cDNA EST yk302g12.5 comes from this gene; cDNA EST 15907U68138 Human PSD-95 2e−010 4521241 (AB024927) 2e−022 mRNA, partialCsENDO-3 cds [Ciona savignyi] 15908 U88827 Aotus trivirgatus 6e−0113914810 RIBONUCLEASE 1e−016 ribonuclease K6 precursor gene, PRECURSORcomplete cds (RNASE K6) >gi|2745760 (AF037086) ribonuclease k6 precursor15909 AF045573 Mus musculus 2e−012 3025718 (AF045573) 3e−016 FLI-LRRFLI-LRR associated associated protein-1 protein-1 [Mus mRNA, musculus]complete cds 15910 NM_001365.1 Homo sapiens 2e−012 4521241 (AB024927)5e−020 discs, large CsENDO-3 (Drosophila) [Ciona savignyil] homolog 4(DLG4) mRNA > :: gb|U83192|HS U83192 Homo sapiens post- synaptic densityprotein 95 (PSD95) mRNA, complete cds 15911 U28049 Human TBX2 7e−0132501115 TBX2 2e−011 (TXB2) mRNA, PROTEIN (T- complete cds. BOX PROTEIN2) 15912 M23404 Chicken 2e−013 726403 (U23175) 1e−025 erythrocytesimilar to anion anion transport exchange protein (band3) protein mRNA,[Caenorhabditis complete cds. elegans] 15913 AF005963 Homo sapiens1e−014 104270 Ig heavy chain - 1.9 XY homologous clawed frog region,partial sequence 15914 M29863 Human farnesyl 9e−015 182405 (M29863)0.005 pyrophosphate farnesyl synthetase pyrophosphate mRNA synthetase[Homo sapiens] 15915 D28126 Human gene for 3e−015 <NONE> <NONE> <NONE>ATP synthase alpha subunit, complete cds (exon 1 to 12) 15916 Z80150 H.sapiens 3e−015 3387914 (AF070550) 3.5 CACNL1A4 cote1 [Homo gene, exons41 sapiens] and 42 > :: emb|A70716.1| A70716 Sequence 37 from PatentWO9813490 15917 U28049 Human TBX2 4e−016 2501116 TBX2 6e−009 (TXB2)mRNA, PROTEIN (T- complete cds. BOX PROTEIN 2) tbx gene [Mus musculus]15918 U31629 Mus musculus 1e−017 3024998 HYPOTHETICAL 3e−017 C2C12unknown HEART mRNA, partial PROTEIN cds. 15919 J05262 Human farnesyl1e−018 182405 (M29863) 0.0001 pyrophosphate farnesyl synthetasepyrophosphate mRNA, synthetase complete cds. [Homo sapiens] 15920 D28126Human gene for 5e−019 <NONE> <NONE> <NONE> ATP synthase alpha subunit,complete cds (exon 1 to 12) 15921 D28126 Human gene for 5e−019 3219984HYPOTHETICAL 5.7 ATP synthase PROTEIN alpha subunit, MJ1597.1 completecds region (exon 1 to 12) MJ1597.1 [Methanococcus jannaschii] 15922NM_004587.1 Homo sapiens 2e−019 4759056 ribosome 0.004 ribosome bindingprotein binding protein 1 (dog 180 kD 1 (dog 180 kD homolog)homolog) >gi|3299885 (RRBP1) (AF006751) mRNA > :: ES/130 [Homogb|AF006751| sapiens] AF006751 Homo sapiens ES/130 mRNA, complete cds15923 U89915 Mus musculus 5e−020 3462455 (U89915) 2e−005 junctionaljunctional adhesion adhesion molecule (Jam) molecule [Mus mRNA,musculus] complete cds 15924 AF045573 Mus musculus 5e−020 3025718(AF045573) 9e−025 FLI-LRR FLI-LRR associated associated protein-1protein-1 [Mus mRNA, musculus] complete cds 15925 NM_004587.1 Homosapiens 2e−020 4759056 ribosome 0.0008 ribosome binding protein bindingprotein 1 (dog 180 kD 1 (dog 180 kD homolog) homolog) >gi|3299885(RRBP1) (AF006751) mRNA > :: ES/130 [Homo gb|AF006751| sapiens] AF006751Homo sapiens ES/130 mRNA, complete cds 15926 AF051098 Mus musculus2e−021 3858883 (U67056) 0.002 seven myosin I heavy transmembrane chainkinase domain orphan [Acanthamoeba receptor mRNA, castellanii] completecds >gi|4206769 (AF104910) myosin I heavy chain kinase [Acanthamoebacastellanii] 15927 AF051098 Mus musculus 2e−021 3858883 (U67056) 0.001seven myosin I heavy transmembrane chain kinase domain orphan[Acanthamoeba receptor mRNA, castellanii] complete cds >gi|4206769(AF104910) myosin I heavy chain kinase [Acanthamoeba castellanii] 15928M13519 Human N- 2e−021 4504373 hexosaminidase 2e−007 acetyl-beta- B(beta glucosaminidase polypeptide) (HEXB) >gi|123081|sp mRNA, 3′ end.|P07686|HEXB_(—) HUMAN BETA- HEXOSAMINIDASE BETA CHAIN PRECURSOR beta-N-acetylhexosaminidase (EC 3.2.1.52) beta chain - human >gi|386770(M23294) beta- hexosaminidase beta-subunit [Homo sapiens] 15929 Z81014Human DNA 2e−022 <NONE> <NONE> <NONE> sequence from cosmid U65A4,between markers DXS366 and DXS87 on chromosome X* 15930 AF147311.1 Homosapiens 2e−022 3875904 (Z70207) 0.07 full length insert predicted usingcDNA clone Genefinder; YA82F10 similar to collagen; cDNA EST EMBL:D65905 comes from this gene; cDNA EST EMBL: D65858 comes from this gene;cDNA EST EMBL: D69306 comes from this gene; cDNA EST EMBL: D65755 comesfrom this gen... 15931 AF037088 Gorilla gorilla 9e−024 3914791RIBONUCLEASE 3e−019 ribonuclease k6 K6 precursor, gene, PRECURSORcomplete cds (RNASE K6) >gi|2745752 (AF037082) ribonuclease k6 precursor15932 Z81014 Human DNA 8e−024 <NONE> <NONE> <NONE> sequence from cosmidU65A4, between markers DXS366 and DXS87 on chromosome X* 15933 AF037088Gorilla gorilla 9e−025 3914810 RIBONUCLEASE 4e−018 ribonuclease k6 K6precursor, gene, PRECURSOR complete cds (RNASE K6) >gi|2745760(AF037086) ribonuclease k6 precursor 15934 AF147311.1 Homo sapiens1e−026 131413 PULMONARY 0.059 full length insert SURFACTANT- cDNA cloneASSOCIATED YA82F10 PROTEIN A PRECURSOR (SP-A) (PSP-A) (PSAP) precursor -rabbit >gi|165706 (J03542) apoprotein of surfactant [Oryctolaguscuniculus] 15935 Z46786 D. melanogaster 1e−027 1079042 acetyl-CoA 4e−025mRNA for synthetase - fruit acetyl-CoA fly synthetase 15936 NM_004039.1Homo sapiens 4e−028 450448 (M33322) 0.1 annexin II calpactin I(lipocortin II) heavy chain for lipocortin II, [Mus musculus] completecds 15937 X53064 Homo sapiens 1e−028 134846 SMALL 0.005 SPRR2A genePROLINE- encoding small RICH proline rich PROTEIN II protein richprotein [Homo sapiens] 15938 M29863 Human farnesyl 1e−028 4503685farnesyl 2e−008 pyrophosphate diphosphate synthetase synthase mRNAdimethylallyltranstransferase, geranyltranstransferase) bp313 to bp1374is almost identical to human farnesyl pyrophosphate synthetase mRNA.[Homo sapiens] 15939 Z18950 H. sapiens genes 5e−029 2493898 DOPAMINE-1.4 for S100E BETA- calcium binding MONOOXYGE protein, CAPL, NASE andS100D PRECURSOR calcium binding (DOPAMINE protein EF- BETA- Hand patentUS HYDROXYLASE) 5789248 (DBH) 1.14.17.1) precursor -mouse >gi|260873|bbs |119249 621 aa] [Mus sp.] 15940 M19481 Human 5e−030<NONE> <NONE> <NONE> follistatin gene, exon 6. 15941 AF007155 Homosapiens 2e−032 4502641 chemokine (C- 1.6 clone 23763 C) receptor 7unknown TYPE 7 mRNA, partial PRECURSOR cds (C-C CKR-7) (CC-CKR-7)(CCR-7) (MIP-3 BETA RECEPTOR) (EBV- INDUCED G PROTEIN- COUPLEDRECEPTOR 1) (EBI1) (BLR2) >gi|1082381|Pir ∥B55735 lymphocyte- specificG- protein-coupled receptor EBI1 - human >gi|468316 (L3158 15942 M99624Human 8e−034 294845 (L13655) 9e−014 epidermal membrane growth factorprotein receptor-related [Saccharum gene, 5′ end. hybrid cultivarH65-7052] 15943 U49082 Human 8e−035 1840045 (U49082) 1e−014 transportertransporter protein (g17) protein [Homo mRNA, sapiens] complete cds15944 D50369 Homo sapiens 9e−036 3024781 UBIQUINOL- 0.0002 mRNA for lowCYTOCHROME C molecular mass REDUCTASE ubiquinone- COMPLEX bindingprotein, UBIQUINONE- complete cds BINDING PROTEIN QP- C PROTEIN)(COMPLEX III SUBUNIT VII) ubiquinone- binding protein [Homo sapiens]15945 AF086313 Homo sapiens 9e−036 2832777 (AL021086)/ 1e−039 fulllength insert prediction = cDNA clone (method:; comes ZD52B10 from the5′ UTR [Drosophila melanogaster] 15946 NM_004074.1 Homo sapiens 1e−0382499854 PROBABLE 2 cytochrome c PEPTIDASE oxidase subunit Y4SO VIII(COX8), >gi|2182630 nuclear gene encoding mitochondrial protein, mRNA >:: gb|J04823|HU MCOX8A Human cytochrome c oxidase subunit VIII (COX8)mRNA, complete cds. 15947 AB024436.1 Homo sapiens 2e−041 3132900(AF038662) 4e−016 mRNA for beta- beta-1,4- 1,4- galactosyltransferasegalactosyltransferase [Homo IV, sapiens] beta- complete cds 1,4-galactosyltransferase IV [Homo sapiens] 15948 AF057734 Homo sapiens2e−043 2842416 (AL008730) 3e−062 17-beta- dJ487J7.1.1 hydroxysteroid(putative protein dehydrogenase dJ487J7.1 IV (HSD17B4) isoform 1) gene,exon 16 [Homo sapiens] 15949 Z69650.1 Human DNA 2e−044 1872200 (U22376)1e−008 sequence from alternatively cosmid L69F7B, spliced productHuntington's using exon 13A Disease Region, chromosome 4p16.3 containsHuntington Disease (HD) gene 15950 NM_003938.1 Homo sapiens 2e−0443478639 (AC005545) 3e−016 adaptin, delta delta-adaptin, (ADTD) mRNApartial CDS > :: [Homo sapiens] gb|U91930|HS U91930 Homo sapiens AP-3complex delta subunit mRNA, complete cds 15951 AF026029 Homo sapiens8e−045 1916930 (U88570) 7.6 poly(A) binding CREB-binding protein IIprotein homolog (PABP2) gene, [Drosophila complete cds melanogaster]15952 AB006622 Homo sapiens 1e−045 73404 E2 protein - 0.11 mRNA forhuman KIAA0284 papillomavirus gene, partial cds type 5 15953 U90918Human clone 1e−048 3877568 (Z70208) 0.042 23654 mRNA similar to sequencecollagen 15954 AB006622 Homo sapiens 1e−049 73404 E2 protein - 0.11 mRNAfor human KIAA0284 papillomavirus gene, partial cds type 5 15955AL049258.1 Homo sapiens 1e−050 <NONE> <NONE> <NONE> mRNA; cDNADKFZp564E173 (from clone DKFZp564E173) 15956 AF022367 Homo sapiens5e−051 3132900 (AF038662) 6e−019 beta-1,4- beta-1,4-galactosyltransferase galactosyltransferase mRNA, [Homo complete cdssapiens] beta- 1,4- galactosyltransferase IV [Homo sapiens] 15957AF057734 Homo sapiens 7e−053 2842416 (AL008730) 6e−055 17-beta-dJ487J7.1.1 hydroxysteroid (putative protein dehydrogenase dJ487J7.1 IV(HSD17B4) isoform 1) gene, exon 16 [Homo sapiens] 15958 AF097709 Homosapiens 8e−055 4506141 protease, serine, 2e−017 serine protease 11 (IGF(PRSS11) binding) mRNA, partial >gi|1513059|dbj cds |BAA13322| (D87258)serin protease with IGF-binding motif [Homo sapiens] protease, PRSS11[Homo sapiens] 15959 U31629 Mus musculus 9e−057 3025215 HYPOTHETICAL5e−033 C2C12 unknown 81.0 KD mRNA, partial PROTEIN cds. C35D10.4 INCHROMOSOME III >gi|2146877|pir ∥S72572 probable ABC1 protein homolog -Caenorhabditis elegans protein (Swiss-Prot Acc: P27697) [Caenorhabditiselegans] 15960 AB006622 Homo sapiens 8e−057 73404 E2 protein - 1.7 mRNAfor human KIAA0284 papillomavirus gene, partial cds type 5 15961AF025439 Homo sapiens 4e−059 <NONE> <NONE> <NONE> Opa-interactingprotein OIP3 mRNA, partial cds 15962 M99624 Human 1e−060 123364SEGMENTATION 5.3 epidermal PROTEIN growth factor EVEN- receptor-relatedSKIPPED fly gene, 5′ end. (Drosophila sp.) >gi|157387 (M14767) even-skipped gene [Drosophila melanogaster] 15963 AF045573 Mus musculus5e−061 3025718 (AF045573) 7e−029 FLI-LRR FLI-LRR associated associatedprotein-1 protein-1 [Mus mRNA, musculus] complete cds 15964 AB006622Homo sapiens 2e−062 2119133 ribosomal 2e−015 mRNA for protein S17 - catKIAA0284 (fragment) gene, partial cds musculus] 15965 M30702 Human2e−063 4502199 amphiregulin 0.0002 amphiregulin (schwannoma- (AR) gene,exon derived growth 5, clones factor) lambda- >gi|113754|sp| ARH(6,12).P15514|AMP R_HUMAN AMPHIREGULIN PRECURSOR (AR) (COLORECTUM CELL- DERIVEDGROWTH FACTOR) (CRDGF) >gi|107391|pir|| A34702 amphiregulin precursor -human >gi|178890 (M30703) amphiregulin [Homo sapien 15966 L38847 Musmusculus 6e−064 3861228 (AJ235272) 2.9 hepatoma unknown transmembrane[Rickettsia kinase ligand prowazekii] Sequence 1 from patent US 562489915967 L38847 Mus musculus 6e−064 3861228 (AJ235272) 2.9 hepatoma unknowntransmembrane [Rickettsia kinase ligand prowazekii] Sequence 1 frompatent US 5624899 15968 Z78141 M. musculus 8e−066 1490324 (Z78141)8e−019 partial cochlear unknown [Mus mRNA (clone musculus] 29C9) 15969X12650 Mus musculus 2e−072 833602 (X54277) 7e−022 gene for beta- cardiactropomyosin tropomyosin [Coturnix coturnix] 15970 M87635 Mouse beta-2e−084 1216293 (L35239) 5e−019 tropomyosin 2 cardiac mRNA, tropomyosincomplete cds. [Xenopus laevis] 15971 M13364 Rabbit calcium- 2e−084115611 CALCIUM- 1e−058 dependent DEPENDENT protease, small PROTEASE,subunit mRNA, SMALL complete cds. NEUTRAL PROTEINASE)(CANP) >gi|108563|pir|| A34466 calpain (EC 3.4.22.17) II light chain -bovine 3.4.22.17) [Bos taurus] 15972 M87635 Mouse beta- 3e−088 1216293(L35239) 9e−028 tropomyosin 2 cardiac mRNA, tropomyosin complete cds.[Xenopus laevis] 15973 M87635 Mouse beta- 5e−092 1216293 (L35239) 2e−035tropomyosin 2 cardiac mRNA, tropomyosin complete cds. [Xenopus laevis]15974 X85992 M. musculus 8e−097 2137756 semaphorin C - 2e−048 mRNA formouse semaphorin C (fragment) musculus] 15975 M24103 Bovine e−103 113463ADP, ATP 2e−035 ADP/ATP CARRIER translocase T2 PROTEIN, mRNA, LIVERcomplete cds. ISOFORM T2 (ADP/ATP TRANSLOCASE 3) (ADENINE NUCLEOTIDETRANSLOCATOR 3) (ANT 3) >gi|86757|pir|| S03894 ADP, ATP carrier proteinT2 - human 15976 U48852 Cricetulus e−107 1216486 (U48852) HT 3e−057griseus HT protein protein mRNA, [Cricetulus complete cds. griseus]15977 X76168 R. norvegicus e−112 544118 GAP 1e−063 mRNA for JUNCTIONconnexin 30.3 BETA-5 PROTEIN (CONNEXIN 30.3) (CX30.3) >gi|481577|pir||S38891 connexin 30.3 - rat >gi|431204|emb| CAA53762| (X76168) connexin30.3 15978 X76168 R. norvegicus e−115 461864 GAP 7e−064 mRNA forJUNCTION connexin 30.3 BETA-5 PROTEIN junction protein Cx30.3 -mouse >gi|192647 (M91443) connexin 30.3 [Mus musculus] 15979 AJ009634.1Mus musculus e−137 4138203 (AJ009634) 5e−065 fjx1 gene Fjx1 [Musmusculus] 15980 X76168 R. norvegicus e−130 544118 GAP 2e−074 mRNA forJUNCTION connexin 30.3 BETA-5 PROTEIN (CONNEXIN 30.3)(CX30.3) >gi|481577|pir|| S38891 connexin 30.3 - rat >gi|431204|emb|CAA53762| (X76168) connexin 30.3

Example 79 Differential Expression of Polynucleotides of the Invention:Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the inventionwas assessed in several libraries prepared from various sources,including primary cells, cell lines and patient tissue samples. Table122 provides a summary of these libraries, including the shortenedlibrary name (used hereafter), the mRNA source used to prepared the cDNAlibrary, the “nickname” of the library that is used in the tables below(in quotes), and the approximate number of clones in the library. TABLE122 Description of cDNA Libraries Number of Library Clones in (Lib#)Description Library 1 Human Colon Cell Line Km12 L4: High Metastatic308731 Potential (derived from Km12C) 2 Human Colon Cell Line Km12C: LowMetastatic Potential 284771 3 Human Breast Cancer Cell Line MDA-MB-231:High 326937 Metastatic Potential; micro-mets in lung 4 Human BreastCancer Cell Line MCF7: Non Metastatic 318979 8 Human Lung Cancer CellLine MV-522: High Metastatic 223620 Potential 9 Human Lung Cancer CellLine UCP-3: Low Metastatic 312503 Potential 12 Human microvascularendothelial cells (HMVEC) - 41938 UNTREATED (PCR (OligodT) cDNA library)13 Human microvascular endothelial cells (HMVEC) - bFGF 42100 TREATED(PCR (OligodT) cDNA library) 14 Human microvascular endothelial cells(HMVEC) - 42825 VEGF TREATED (PCR (OligodT) cDNA library) 15 NormalColon - UC#2 Patient (MICRODISSECTED PCR 282722 (OligodT) cDNA library)16 Colon Tumor - UC#2 Patient (MICRODISSECTED PCR 298831 (OligodT) cDNAlibrary) 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467(MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3Patient (MICRODISSECTED PCR 36216 (OligodT) cDNA library) 19 ColonTumor - UC#3 Patient (MICRODISSECTED PCR 41388 (OligodT) cDNA library)20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956(MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived fromnormal prostate epithelium 164801 22 WOca Cells derived from GleasonGrade 4 prostate cancer 162088 epithelium 23- Normal Lung Epithelium ofPatient #1006 306198 (MICRODISSECTED PCR (OligodT) cDNA library) 24Primary tumor, Large Cell Carcinoma of Patient #1006 309349(MICRODISSECTED PCR (OligodT) cDNA library)

The KM12L4 cell line is derived from the KM12C cell line (Morikawa, etal., Cancer Research (1988) 48:6863). The KM12C cell line, which ispoorly metastatic (low metastatic) was established in culture from aDukes' stage B₂ surgical specimen (Morikawa et al. Cancer Res. (1988)48:6863). The KML4-A is a highly metastatic subline derived from KM12C(Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc.Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C andKM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) arewell-recognized in the art as a model cell line for the study of coloncancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. CancerRes. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin.Exp. Metastasis (1996) 14:246). The MDA-MB-231 cell line (Brinkley etal. Cancer Res. (1980) 40:3118-3129) was originally isolated frompleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), isof high metastatic potential, and forms poorly differentiatedadenocarcinoma grade II in nude mice consistent with breast carcinoma.

The MCF7 cell line was derived from a pleural effusion of a breastadenocarcinoma and is non-metastatic. The MV-522 cell line is derivedfrom a human lung carcinoma and is of high metastatic potential. TheUCP-3 cell line is a low metastatic human lung carcinoma cell line; theMV-522 is a high metastatic variant of UCP-3. These cell lines arewell-recognized in the art as models for the study of human breast andlung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870(MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965(MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586(MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116(MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3);Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki etal., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., AnticancerRes (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997)8:696 (MV522)). The samples of libraries 15-20 are derived from twodifferent patients (UC#2, and UC#3). The bFGF-treated HMVEC wereprepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treatedHMVEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs.Following incubation with the respective growth factor, the cells werewashed and lysis buffer added for RNA preparation. The GRRpz and WOcacells were provided by Dr. Donna M. Peehl, Department of Medicine,Stanford University School of Medicine. GRRpz cells were derived fromnormal prostate epithelium. The WOca cells are Gleason Grade 4 cellline.

Each of the libraries is composed of a collection of cDNA clones that inturn are representative of the mRNAs expressed in the indicated mRNAsource. In order to facilitate the analysis of the millions of sequencesin each library, the sequences were assigned to clusters. The concept of“cluster of clones” is derived from a sorting/grouping of cDNA clonesbased on their hybridization pattern to a panel of roughly 300 7 bpoligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29).Random cDNA clones from a tissue library are hybridized at moderatestringency to 300 7 bp oligonucleotides. Each oligonucleotide has somemeasure of specific hybridization to that specific clone. Thecombination of 300 of these measures of hybridization for 300 probesequals the “hybridization signature” for a specific clone. Clones withsimilar sequence will have similar hybridization signatures. Bydeveloping a sorting/grouping algorithm to analyze these signatures,groups of clones in a library can be identified and brought togethercomputationally. These groups of clones are termed “clusters”. Dependingon the stringency of the selection in the algorithm (similar to thestringency of hybridization in a classic library cDNA screeningprotocol), the “purity” of each cluster can be controlled. For example,artifacts of clustering may occur in computational clustering just asartifacts can occur in “wet-lab” screening of a cDNA library with 400 bpcDNA fragments, at even the highest stringency. The stringency used inthe implementation of cluster herein provides groups of clones that arein general from the same cDNA or closely related cDNAs. Closely relatedclones can be a result of different length clones of the same cDNA,closely related clones from highly related gene families, or splicevariants of the same cDNA.

Differential expression for a selected cluster was assessed by firstdetermining the number of cDNA clones corresponding to the selectedcluster in the first library (Clones in 1^(st)), and the determining thenumber of cDNA clones corresponding to the selected cluster in thesecond library (Clones in 2^(nd)). Differential expression of theselected cluster in the first library relative to the second library isexpressed as a “ratio” of percent expression between the two libraries.In general, the “ratio” is calculated by: 1) calculating the percentexpression of the selected cluster in the first library by dividing thenumber of clones corresponding to a selected cluster in the firstlibrary by the total number of clones analyzed from the first library;2) calculating the percent expression of the selected cluster in thesecond library by dividing the number of clones corresponding to aselected cluster in a second library by the total number of clonesanalyzed from the second library; 3) dividing the calculated percentexpression from the first library by the calculated percent expressionfrom the second library. If the “number of clones” corresponding to aselected cluster in a library is zero, the value is set at 1 to aid incalculation. The formula used in calculating the ratio takes intoaccount the “depth” of each of the libraries being compared, i.e., thetotal number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentiallyexpressed between two samples when the ratio value is greater than atleast about 2, preferably greater than at least about 3, more preferablygreater than at least about 5, where the ratio value is calculated usingthe method described above. The significance of differential expressionis determined using a z score test (Zar, Biostatistical Analysis,Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298(1974).

Using this approach, a number of polynucleotide sequences wereidentified as being differentially expressed between, for example, cellsderived from high metastatic potential cancer tissue and low metastaticcancer cells, and between cells derived from metastatic cancer tissueand normal tissue. Evaluation of the levels of expression of the genescorresponding to these sequences can be valuable in diagnosis,prognosis, and/or treatment (e.g., to facilitate rationale design oftherapy, monitoring during and after therapy, etc.). Moreover, the genescorresponding to differentially expressed sequences described herein canbe therapeutic targets due to their involvement in regulation (e.g.,inhibition or promotion) of development of, for example, the metastaticphenotype. For example, sequences that correspond to genes that areincreased in expression in high metastatic potential cells relative tonormal or non-metastatic tumor cells may encode genes or regulatorysequences involved in processes such as angiogenesis, differentiation,cell replication, and metastasis.

Detection of the relative expression levels of differentially expressedpolynucleotides described herein can provide valuable information toguide the clinician in the choice of therapy. For example, a patientsample exhibiting an expression level of one or more of thesepolynucleotides that corresponds to a gene that is increased inexpression in metastatic or high metastatic potential cells may warrantmore aggressive treatment for the patient. In contrast, detection ofexpression levels of a polynucleotide sequence that corresponds toexpression levels associated with that of low metastatic potential cellsmay warrant a more positive prognosis than the gross pathology wouldsuggest.

The differential expression of the polynucleotides described herein canthus be used as, for example, diagnostic markers, prognostic markers,for risk assessment, patient treatment and the like. Thesepolynucleotide sequences can also be used in combination with otherknown molecular and/or biochemical markers.

The differential expression data for polynucleotides of the inventionthat have been identified as being differentially expressed acrossvarious combinations of the libraries described above is summarized inTable 123 (inserted prior to the claims). Table 123 provides: 1) theSequence Identification Number (“SEQ ID”) assigned to thepolynucleotide; 2) the cluster (“CLUST”) to which the polynucleotide hasbeen assigned as described above; 3) the library comparisons thatresulted in identifcation of the polynucleotide as being differentiallyexpressed (“PairAB-text”), with shorthand names of the comparedlibraries provided in parentheses following the library numbers; 4) thenumber of clones corresponding to the polynucleotide in the firstlibrary listed (“A”); 5) the number of clones corresponding to thepolynucleotide in the second library listed (“B”); 6) the “RATIO PLUS”where the comparison resulted in a finding that the number of clones inlibrary A is greater than the number of clones in library B; and 7) the“RATIO MINUS” where the comparison resulted in a finding that the numberof clones in library B is greater than the number of clones in libraryA. TABLE 123 SEQ CLONES CLONES RATIO RATIO ID CLUST PairAB-text in A inB PLUS MINUS 15670 819498 _21, 22 (Normal Prostate vs. 6 0 5.9 CancerousProstate) 15674 728115 _15, 16 (Normal Colon vs. 0 7 6.62 Colon Tumor)_16, 17 (Colon Tumor vs. 7 0 7.11 Colon Metastasis) 15675 372700 _08, 09(Lung, High Metastatic 3 50 11.93 Potential vs. Lung, Low MetastaticPotential) _19, 20 (Colon Tumor vs. 8 0 5.98 Colon Tumor Metastasis)15678 729832 _15, 16 (Normal Colon vs. 0 11 10.41 Colon Tumor) _16, 17(Colon Tumor vs. 11 0 11.17 Colon Metastasis) 15679 505514 _23, 24(Normal Lung vs. Lung 26 10 2.63 Tumor) 15683 549934 _21, 22 (NormalProstate vs. 8 0 7.87 Cancerous Prostate) _16, 17 (Colon Tumor vs. 3 206.56 Colon Metastasis) _15, 16 (Normal Colon vs. 11 3 3.88 Colon Tumor)15691 450399 _15, 16 (Normal Colon vs. 28 68 2.3 Colon Tumor) _15, 17(Normal Colon vs. 28 117 3.89 Colon Metastasis) 15692 450982 _16, 17(Colon Tumor vs. 14 32 2.25 Colon Metastasis) 15694 379302 _21, 22(Normal Prostate vs. 8 1 7.87 Cancerous Prostate) 15709 817503 _21, 22(Normal Prostate vs. 18 4 4.43 Cancerous Prostate) 15714 830085 _21, 22(Normal Prostate vs. 0 9 9.15 Cancerous Prostate) 15718 830931 _21, 22(Normal Prostate vs. 0 7 7.12 Cancerous Prostate) 15721 819046 _21, 22(Normal Prostate vs. 2 13 6.61 Cancerous Prostate) 15724 728115 _15, 16(Normal Colon vs. 0 7 6.62 Colon Tumor) _16, 17 (Colon Tumor vs. 7 07.11 Colon Metastasis) 15731 553242 _16, 17 (Colon Tumor vs. 0 6 5.91Colon Metastasis) 15737 820061 _21, 22 (Normal Prostate vs. 1 20 20.33Cancerous Prostate) 15744 220584 _08, 09 (Lung, High Metastatic 1 128.59 Potential vs. Lung, Low Metastatic Potential) 15746 549934 _16, 17(Colon Tumor vs. 3 20 6.56 Colon Metastasis) _15, 16 (Normal Colon vs.11 3 3.88 Colon Tumor) _21, 22 (Normal Prostate vs. 8 0 7.87 CancerousProstate) 15752 819460 _21, 22 (Normal Prostate vs. 18 1 17.7 CancerousProstate) 15761 551785 _21, 22 (Normal Prostate vs. 0 6 6.1 CancerousProstate) 15762 17092 _03, 04 (Breast, High 0 25 25.62 MetastaticPotential vs. Breast, Non- Metastatic) 15765 745559 _21, 22 (NormalProstate vs. 1 9 9.15 Cancerous Prostate) 15767 379879 _21, 22 (NormalProstate vs. 0 9 9.15 Cancerous Prostate) 08, 09 (Lung, High Metastatic0 13 9.3 Potential vs. Lung, Low Metastatic Potential) 15773 268290 _21,22 (Normal Prostate vs. 33 69 2.13 Cancerous Prostate) 15774 818043 _21,22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15780 450247 _21, 22(Normal Prostate vs. 23 8 2.83 Cancerous Prostate) 15781 819273 _21, 22(Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15782 587779 _21, 22(Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15784 615617 _21, 22(Normal Prostate vs. 0 7 7.12 Cancerous Prostate) 15787 818682 _21, 22(Normal Prostate vs. 11 2 5.41 Cancerous Prostate) 15789 484413 _21, 22(Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15790 819273 _21, 22(Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15793 818682 _21, 22(Normal Prostate vs. 11 2 5.41 Cancerous Prostate) 15797 819273 _21, 22(Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15813 820061 _21, 22(Normal Prostate vs. 1 20 20.33 Cancerous Prostate) 15819 375958 _21, 22(Normal Prostate vs. 2 11 5.59 Cancerous Prostate) _08, 09 (Lung, HighMetastatic 0 9 6.44 Potential vs. Lung, Low Metastatic Potential) 15821831049 _21, 22 (Normal Prostate vs. 0 11 11.18 Cancerous Prostate) 15823553200 _21, 22 (Normal Prostate vs. 0 6 6.1 Cancerous Prostate) 15824139677 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15825139677 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15829375958 _08, 09 (Lung, High Metastatic 0 9 6.44 Potential vs. Lung, LowMetastatic Potential) _21, 22 (Normal Prostate vs. 2 11 5.59 CancerousProstate) 15834 831812 _21,22 (Normal Prostate vs. 0 7 7.12 CancerousProstate) 15842 193373 _21, 22 (Normal Prostate vs. 6 0 5.9 CancerousProstate) 15843 400619 _08, 09 (Lung, High Metastatic 6 0 8.38 Potentialvs. Lung, Low Metastatic Potential) 15844 831149 _21, 22 (NormalProstate vs. 0 7 7.12 Cancerous Prostate) 15846 817503 _21, 22 (NormalProstate vs. 18 4 4.43 Cancerous Prostate) 15853 648679 _23, 24 (NormalLung vs. Lung 11 1 11.11 Tumor) _16, 17 (Colon Tumor vs. 79 0 80.23Colon Metastasis) _15, 17 (Normal Colon vs. 7 0 7.51 Colon Metastasis)_15, 16 (Normal Colon vs. 7 79 10.68 Colon Tumor) 15856 373928 _21, 22(Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15861 373928 _21, 22(Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15864 372700 _19, 20(Colon Tumor vs. 8 0 5.98 Colon Tumor Metastasis) _08, 09 (Lung, HighMetastatic 3 50 11.93 Potential vs. Lung, Low Metastatic Potential)15870 379105 _15, 16 (Normal Colon vs. 0 8 7.57 Colon Tumor) 15871831188 _21, 22 (Normal Prostate vs. 0 8 8.13 Cancerous Prostate) 15875831812 _21, 22 (Normal Prostate vs. 0 7 7.12 Cancerous Prostate) 15879831026 _21, 22 (Normal Prostate vs. 0 10 10.17 Cancerous Prostate) 15881380207 _21, 22 (Normal Prostate vs. 0 6 6.1 Cancerous Prostate) _08, 09(Lung, High Metastatic 0 8 5.72 Potential vs. Lung, Low MetastaticPotential) 15882 819460 _21, 22 (Normal Prostate vs. 18 1 17.7 CancerousProstate) 15890 819201 _21, 22 (Normal Prostate vs. 6 0 5.9 CancerousProstate) 15891 374826 _15, 17 (Normal Colon vs. 5 20 3.73 ColonMetastasis) _08, 09 (Lung, High Metastatic 38 132 2.49 Potential vs.Lung, Low Metastatic Potential) _15, 16 (Normal Colon vs. 5 18 3.41Colon Tumor) 15897 553242 _16, 17 (Colon Tumor vs. 0 6 5.91 ColonMetastasis) 15912 220584 _08, 09 (Lung, High Metastatic 1 12 8.59Potential vs. Lung, Low Metastatic Potential) 15914 819498 _21, 22(Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15919 819498 _21, 22(Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15922 831160 _21, 22(Normal Prostate vs. 0 12 12.2 Cancerous Prostate) 15925 831160 _21, 22(Normal Prostate vs. 0 12 12.2 Cancerous Prostate) 15928 373298 _15, 17(Normal Colon vs. 126 42 3.22 Colon Metastasis) _15, 16 (Normal Colonvs. 126 59 2.26 Colon Tumor) 15936 450262 _21, 22 (Normal Prostate vs. 08 8.13 Cancerous Prostate) 15937 484703 _21, 22 (Normal Prostate vs. 280 27.54 Cancerous Prostate) 15938 819498 _21, 22 (Normal Prostate vs. 60 5.9 Cancerous Prostate) 15939 406043 _21, 22 (Normal Prostate vs. 0 66.1 Cancerous Prostate) 15940 817500 _21, 22 (Normal Prostate vs. 2 189.15 Cancerous Prostate) 15941 818180 _21, 22 (Normal Prostate vs. 2 105.08 Cancerous Prostate) 15946 429009 _21, 22 (Normal Prostate vs. 8 17.87 Cancerous Prostate) 15950 383021 _21, 22 (Normal Prostate vs. 3 124.07 Cancerous Prostate) 15955 831580 _21, 22 (Normal Prostate vs. 0 66.1 Cancerous Prostate) 15977 763446 _21, 22 (Normal Prostate vs. 11 110.82 Cancerous Prostate) 15978 763446 _21, 22 (Normal Prostate vs. 11 110.82 Cancerous Prostate) 15980 763446 _21, 22 (Normal Prostate vs. 11 110.82 Cancerous Prostate) 15981 10154 _3, 4 (Breast, High Metastatic 3317 108.1 Potential vs. Breast, Low Metastatic)

Example 80 Differential Expression of a Polynucleotides Associated withMetastatic Potential in Breast Cancer

Differential expression was examined in breast cancer cells havingeither high metastatic potential or low metastatic potential. A singlecluster, Cluster Identification No. 10154, was identified as displayinglow expression in the high metastatic potential breast cancer cells(Library 3), and significantly increased expression—approximately100-fold higher—in the low metastatic potential cells (Library 4).Specifically, three clones were identified that were expressed inLibrary 3, the high metastatic potential breast cancer library, while317 clones were expressed in Library 4, the low metastatic potentialbreast cancer library. The two sequences assigned to this particularcluster, SEQ ID NO:1598 land SEQ ID NO:15982, both displayed thisdifferential expression, suggesting that the two sequences are likelyassociated with a single transcript.

SEQ ID NO: 15981 and SEQ ID NO: 15982 were then used as query sequencesto search for homologous sequences in GenBank as described above. SEQ IDNO: 15981 displayed identity to the GenBank entry H72034 (SEQ ID NO:15983) and SEQ ID NO: 15982 displayed identity to GenBank entry AA707002(SEQ ID NO: 15984). SEQ ID NO: 15981 displays striking identity to the3′ end of SEQ ID NO: 15983 (See FIGS. 1A and 1B), while SEQ ID NO: 15982displays striking identity to the 5′ end of SEQ ID NO: 15984 (See FIG.2). Clones of H72034 and AA707002 were ordered from the I.M.A.G.E.Consortium at the Lawrence Livermore National Laboratories (Livermore,Calif.) for further studies.

Restriction Mapping of Clones H72034 and AA707002

The newly identified sequences were digested with a number of differentrestriction endonucleases to construct a restriction map of each of theclones. An appropriate amount of each clone, SEQ ID NO: 15983 or SEQ IDNO: 15984, was digested with various enzymes, and the restrictionfragments identified as follows: Enzyme #Cuts Positions SEQ ID NO: 15983AluI 5 331 1029 1422 1595 1977 BamHI 2 1836 2089 BstEII 1 936 BstXI 11033 HaeIII 12 145 300 453 497 582 780 1102 1536 1561 1722 1981 2062HinfI 12 5 154 205 325 397 473 610 820 968 1295 1426 2066 KpnI 1 1938MspI 6 78 739 1098 2038 2077 2093 NcoI 2 2013 2058 PstI 1 1501 PvuII 2331 1422 Sau3AI 6 1270 1813 1819 1836 1894 2089 SphI 1 1870 XhoI 1 1413SEQ ID NO: 15984 AluI 9 19 245 367 553 586 874 904 996 1214 BamHI 1 407BglI 1 1056 BglII 1 475 BstEI 1 1108 HaeIII 10 153 348 485 867 518 628780 867 915 1016 1312 HindIII 2 243 872 HinfI 1 1353 KpnI 1 132 MspI 21196 1261 PstI 1 823 PvuII 1 996 Sau3AI 7 66 407 475 504 750 850 1024

The restriction maps based on the identified sites can be used todetermine the position of each clone relative to the genomic sequences,and to confirm the 5′-3′ orientation of the clones.

Amplification and Purification of Transcript

A transcript in this region upregulated in low metastatic cancers whichcontain sequences from SEQ ID NOS: 15983-15986-318 is identified using atechnique such as polymerase chain reaction (PCR) amplification. Basedon the sequences identified and the original sequences of the cluster,primers can be designed to isolate the full length cDNA from a libraryconstructed from the breast cancer cell line with low metastaticpotential.

A cDNA template for use in the amplification reaction is generated fromtotal RNA isolated from the high metastatic breast cell line. RNA isreverse transcribed using oligo-dT primer to generate first strand cDNA.cDNA is synthesized by denaturing 3:1 of total RNA, 2:1 oligo-dT primerat 20:M, and 5:1 DEPC water for 8 minutes at 65° C. followed by reversetranscription at 52° C. for 1 hour in a reaction containing thedenatured RNA/primer plus 4:1 15×cDNA buffer (GibcoBRL), 1 :10.1 Mdithiothreitol, 1 :140 U/l RNAseOUT (GibcoBRL), 1:1 DEPC water, 2:110 mMdNTP (GibcoBRL), and 1:115 U/l Thermoscript reverse transcriptase(GibcoBRL). The reaction was terminated by a 5-min incubation at 85° C.,and the RNA was removed by 1:12 U/l RNAse H at 37° C. for thirtyminutes.

Based on the determined orientation of the clones, primers are designedto amplify a full-length clone corresponding to the differentiallyexpressed transcript in this region. Forward primers that are used toamplify the full-length clone are taken from the 5′ end of SEQ IDNO:15683 as follows: F1 5′-TGGGATATAGTCTCGTGGTGCG-3′ (SEQ ID NO: 15985)F2 5′-TGATTCGATGTCATCAGTCCCG-3′ (SEQ ID NO: 15986)Primer F1 is taken from residues 51-62 of SEQ ID NO: 15983, and primerF2 is taken from residues 212-233 Of SEQ ID NO:15683. Both forwardprimers are near the 5′ end of this sequence.

Reverse Primers are designed using sequences complementary to the 3′ endof clone 10154-3 as follows: R1 5′-TGTGTCACAGCCAGACATGAGC (SEQ ID NO:15987) R2 5′-TGCAAACATACACAGGGACCG (SEQ ID NO: 15988)Primer R1 is based on residues 573-552 of SEQ ID NO:15684, and R2 isbased on residues 399-379 of SEQ ID NO:15684.

PCR is performed using a 5:1 aliquot of the first strand cDNA synthesisreaction, and a primer pair, e.g., F1 and R1, F1 and R2, F2 and R1, orF2 and R2. An open reading frame is amplified using 2:1 of the reversetranscription product as template in a PCR reaction containing 5:1 of10×PCR buffer (GibcoBRL), 1:150 mM Mg₂SO₄, 1:110 mM dNTP, 1:1 F1 or F2primer, 1 μl R1 primer, 2.5 U High Fidelity Platinum Taq DNA polymerase(GibcoBRL), and water to 50:1. The molecule is amplified using 30 roundsof amplification in a thermal cycler at the following temperatures: 1minute at 95° C.; 1 minute at 55° C. and 2 minutes at 72° C. The 30cycles was followed by a 10 minute extension at 72° C.

Following amplification of the sequences, the PCR products are loaded ona 1% TEA gel and subjected to gel purification. One or more bands can beisolated from the gel and the DNA was purified using a QIAquick® GelExtraction Kit (Qiagen, Valencia, Calif.). The purified fragment wascloned into a bacterial vector and transformed into the bacterial strainDH5∀. Following cloning of the purified fragment(s), the DNA can beisolated and sequenced to confirm that a band corresponds to atranscript from this genetic region.

The reactions are carried out with two different 5′ and 3′ primers toincrease the likelihood that the reaction will yield an amplificationproduct. Other primers may also be designed from the predicted 5′ and/or3′ end of the sequence, as will be apparent to one skilled in the artupon reading this disclosure, and thus other primers may be designedfrom the general region of SEQ ID NOS:317 and 318 that may yield betterresults than the disclosed primers.

In order to obtain additional sequences 5′ to the end of a partial cDNA,5′ rapid amplification of cDNA ends (RACE) can be performed to ensurethat the entire transcript has been identified. See PCR Protocols: AGuide to Methods and Applications, (1990) Academic Press, Inc. Followingisolation of a cDNA using the F1-R1 or F2-R1 primer pairs, additionalprimers can be designed to perform RACE. The primers can be designedfrom the sequence of 10154-1 as follows: 5′-TTTAGCAGCACTAATGACTGTGGC-3′(SEQ ID NO: 15989) 5′-CGCCGTGAATTACTGTGGATGG-3′ (SEQ ID NO: 15990)The two RACE primers are designed based residues 286-263 and 396-375 ofSEQ ID NO:15983, respectively.These sequences can be used to obtain any transcript sequences 5′ to theamplification products obtained using the PCR protocol described above.Northern Analysis

Other techniques can be used for confirming differential expression ofthe full-length transcript. For example, a Northern Blot can be used toverify differential expression of SEQ ID NOS:15983 and 15984 in a breastcancer cells with low metastatic potential compared to breast cancercells with high metastatic potential. Northern analysis can beaccomplished by methods well-known in the art. Briefly, RNA isindividually isolated from breast cancer cells having high metastaticpotential and breast cancer cells having low metastatic potential, e.g.,a product such as RNeasy Mini Kits (Qiagen, CA) or NucleoSpin® RNA IIKit (Clontech, Palo Alto, Calif.). The isolated RNA samples are ForNorthern analysis, RNA isolated from the cells was electrophoresed on adenaturing formaldehyde agarose gel and transferred onto a membrane suchas a supported nitrocellulose membrane (Schleicher & Schuell).

Rapid-Hyb buffer (Amersham Life Science, Little Chalfont, England) with5 mg/ml denatured single stranded sperm DNA is pre-warmed to 65° C. andthe RNA blots are pre-hybridized in the buffer with shaking at 65° C.for 30 minutes. Gene-specific DNA probes (50 ng per reaction) labeledwith [α-³²P]dCTP (3000 Ci/mmol, Amersham Pharmacia Biotech Inc.,Piscataway, N.J.) (Prime-It RmT Kit, Stratagene, La Jolla, Calif.) andpurified with ProbeQuant™ G-50 Micro Columns (Amersham Pharmacia BiotechInc.) are added and hybridized to the blots with shaking at 65° C. forovernight. The blots are washed in 2×SSC, 0.1%(w/v) SDS at roomtemperature for 20 minutes, twice in 1×SSC, 0.1%(w/v) SDS at 65° C. for15 minutes, then exposed to Hyperfilms (Amersham Life Science).

Example 81 Identification of Differentially Expressed Genes by ArrayAnalysis with Patient Tissue Samples

Differentially expressed genes corresponding to the polynucleotidesdescribed herein were also identified by microarray hybridizationanalysis using materials obtained from patient tissue samples. Thebiological materials used in these experiments are described below.

Source of Patient Tissue Samples

Normal and cancerous tissues were collected from patients using lasercapture microdissection (LCM) techniques, which techniques are wellknown in the art (see, e.g., Ohyama et al. (2000) Biotechniques29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al.(1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Bucket al. (1996) Science 274:998-1001). Table 127 (inserted following thelast page of the Examples) provides information about each patient fromwhich the samples were isolated, including: the Patient ID and PathReportID, numbers assigned to the patient and the pathology reports foridentification purposes; the anatomical location of the tumor(AnatomicalLoc); The Primary Tumor Size; the Primary Tumor Grade; theHistopathologic Grade; a description of local sites to which the tumorhad invaded (Local Invasion); the presence of lymph node metastases(Lymph Node Metastasis); incidence of lymph node metastases (provided asnumber of lymph nodes positive for metastasis over the number of lymphnodes examined) (Incidence Lymphnode Metastasis); the Regional LymphnodeGrade; the identification or detection of metastases to sites distant tothe tumor and their location (Distant Met & Loc); a description of thedistant metastases (Description Distant Met); the grade of distantmetastasis (Distant Met Grade); and general comments about the patientor the tumor (Comments). Adenoma was not described in any of thepatients. adenoma dysplasia (described as hyperplasia by thepathologist) was described in Patient ID No. 695. Extranodal extensionswere described in two patients, Patient ID Nos. 784 and 791.Lymphovascular invasion was described in seven patients, Patient ID Nos.128, 278, 517, 534, 784, 786, and 791. Crohn's-like infiltrates weredescribed in seven patients, Patient ID Nos. 52, 264, 268, 392, 393,784, and 791.

Source of Polynucleotides on Arrays

Polynucleotides on Arrays

Polynucleotides spotted on the arrays were generated by PCRamplification of clones derived from cDNA libraries. The clones used foramplification were either the clones from which the sequences describedherein were derived, or are clones having inserts with significantpolynucleotide sequence overlap with the sequences described herein (SEQID NO:15667-15982) as determined by BLAST2 homology searching.

Microarray Design

Each array used in the examples below had an identical spatial layoutand control spot set. Each microarray was divided into two areas, eacharea having an array with, on each half, twelve groupings of 32×12 spotsfor a total of about 9,216 spots on each array. The two areas arespotted identically which provide for at least two duplicates of eachclone per array. Spotting was accomplished using PCR amplified productsfrom 0.5 kb to 2.0 kb and spotted using a Molecular Dynamics Gen IIIspotter according to the manufacturer's recommendations. The first rowof each of the 24 regions on the array had about 32 control spots,including 4 negative control spots and 8 test polynucleotides.

The test polynucleotides were spiked into each sample before thelabeling reaction with a range of concentrations from 2-600 pg/slide andratios of 1:1. For each array design, two slides were hybridized withthe test samples reverse-labeled in the labeling reaction. This providedfor about 4 duplicate measurements for each clone, two of one color andtwo of the other, for each sample.

Microarray Analysis

cDNA probes were prepared from total RNA isolated from the patient cellsdescribed in above (Table 127). Since LCM provides for the isolation ofspecific cell types to provide a substantially homogenous cell sample,this provided for a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primercontaining a T7 RNA polymerase promoter, followed by second strand DNAsynthesis. cDNA was then transcribed in vitro to produce antisense RNAusing the T7 promoter-mediated expression (see, e.g., Luo et al. (1999)Nature Med 5:117-122), and the antisense RNA was then converted intocDNA. The second set of cDNAs were again transcribed in vitro, using theT7 promoter, to provide antisense RNA. Optionally, the RNA was againconverted into cDNA, allowing for up to a third round of T7-mediatedamplification to produce more antisense RNA. Thus the procedure providedfor two or three rounds of in vitro transcription to produce the finalRNA used for fluorescent labeling. Fluorescent probes were generated byfirst adding control RNA to the antisense RNA mix, and producingfluorescently labeled cDNA from the RNA starting material. Fluorescentlylabeled cDNAs prepared from the tumor RNA sample were compared tofluorescently labeled cDNAs prepared from normal cell RNA sample. Forexample, the cDNA probes from the normal cells were labeled with Cy3fluorescent dye (green) and the cDNA probes prepared from the tumorcells were labeled with Cy5 fluorescent dye (red).

The differential expression assay was performed by mixing equal amountsof probes from tumor cells and normal cells of the same patient. Thearrays were prehybridized by incubation for about 2 hrs at 60° C. in5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twicein isopropanol. Following prehybridization of the array, the probemixture was then hybridized to the array under conditions of highstringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS.After hybridization, the array was washed at 55° C. three times asfollows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2%SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using aMolecular Dynamics Generation III dual color laser-scanner/detector. Theimages were processed using BioDiscovery Autogene software, and the datafrom each scan set normalized to provide for a ratio of expressionrelative to normal. Data from the microarray experiments was analyzedaccording to the algorithms described in U.S. application Ser. No.60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M.Randazzo, and entitled “Precision and accuracy in cDNA microarray data,”which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with theopposite color in order to perform the assay in both “color directions.”Each experiment was sometimes repeated with two more slides (one in eachcolor direction). The level fluorescence for each sequence on the arrayexpressed as a ratio of the geometric mean of 8 replicate spots/genesfrom the four arrays or 4 replicate spots/gene from 2 arrays or someother permutation. The data were normalized using the spiked positivecontrols present in each duplicated area, and the precision of thisnormalization was included in the final determination of thesignificance of each differential. The fluorescent intensity of eachspot was also compared to the negative controls in each duplicated areato determine which spots have detected significant expression levels ineach sample.

A statistical analysis of the fluorescent intensities was applied toeach set of duplicate spots to assess the precision and significance ofeach differential measurement, resulting in a p-value testing the nullhypothesis that there is no differential in the expression level betweenthe tumor and normal samples of each patient. For initial analysis ofthe microarrays, the hypothesis was accepted if p>10⁻³, and thedifferential ratio was set to 1.000 for those spots. All other spotshave a significant difference in expression between the tumor and normalsample. If the tumor sample has detectable expression and the normaldoes not, the ratio is truncated at 1000 since the value for expressionin the normal sample would be zero, and the ratio would not be amathematically useful value (e.g., infinity). If the normal sample hasdetectable expression and the tumor does not, the ratio is truncated to0.001, since the value for expression in the tumor sample would be zeroand the ratio would not be a mathematically useful value. These lattertwo situations are referred to herein as “on/off.” Database tables werepopulated using a 95% confidence level (p>0.05).

Table 128 below summarize the results of the differential expressionanalysis. Each table provides: the SEQ ID NO of the polynucleotidecorresponding to the polynucleotide on the spot on the array; the SpotID (an identifier assigned to the spot so as to distinguish it fromspots on the same and different arrays), the number of patients for whomthere was information obtained from the array (Num Ratios), and thepercentage of patients in which expression was detected at greater thanor equal to a two-fold increase (>=2×), greater than or equal to afive-fold increase (>=5×), or less than or equal to a ½-fold decrease(<=halfx) relative to matched normal control tissue.

In general, a polynucleotide is said to represent a significantlydifferentially expressed gene between two samples when there isdetectable levels of expression in at least one sample and the ratiovalue is greater than at least about 1.2 fold, preferably greater thanat least about 1.5 fold, more preferably greater than at least about 2fold, where the ratio value is calculated using the method describedabove.

A differential expression ratio of 1 indicates that the expression levelof the gene in the tumor cell was not statistically different fromexpression of that gene in normal colon cells of the same patient. Adifferential expression ratio significantly greater than 1 in cancerouscolon cells relative to normal colon cells indicates that the gene isincreased in expression in cancerous cells relative to normal cells,indicating that the gene plays a role in the development of thecancerous phenotype, and may be involved in promoting metastasis of thecell. Detection of gene products from such genes can provide anindicator that the cell is cancerous, and may provide a therapeuticand/or diagnostic target.

Likewise, a differential expression ratio significantly less than 1 incancerous colon cells relative to normal colon cells indicates that, forexample, the gene is involved in suppression of the cancerous phenotype.Increasing activity of the gene product encoded by such a gene, orreplacing such activity, can provide the basis for chemotherapy. Suchgene can also serve as markers of cancerous cells, e.g., the absence ordecreased presence of the gene product in a colon cell relative to anormal colon cell indicates that the cell may be cancerous. TABLE 128SEQ Num ID NO: SpotID Ratios >=2x >=5x <=halfx 15674 579 33 87.88 39.393.03 15678 22300 33 33.33 18.18 6.06 15692 21886 33 33.33 0.00 3.0315730 9487 33 33.33 12.12 3.03 15914 28179 28 32.14 0.00 0.00 1591928179 28 32.14 0.00 0.00 15938 28179 28 32.14 0.00 0.00 15958 9111 3333.33 18.18 3.03 15961 19980 33 33.33 6.06 0.00 15975 23993 33 42.423.03 3.03

Deposit Information. The following materials were deposited with theAmerican Type Culture Collection (CMCC=Chiron Master CultureCollection). TABLE 124 Cell Lines Deposited with ATCC ATCC CMCC CellLine Deposit Date Accession No. Accession No. KM12L4-A Mar. 19, 1998CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15,1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containingspecific clones, were assigned an “ES” number (internal reference) anddeposited with the ATCC. Table 6 below provides the ATCC Accession Nos.of the ES deposits, all of which were deposited on or before May 13,1999. The names of the clones contained within each of these depositsare provided in the Table 126 (inserted before the claims). TABLE 125Pools of Clones and Libraries Deposited with ATCC on or before Mar. 28,2000 Cell Line CMCC ATCC ES75 5140 PTA-1102 ES76 5141 PTA-1103 ES77 5142PTA-1104 ES78 5143 PTA-1105 ES79 5144 PTA-1106 ES80 5145 PTA-1107 ES815146 PTA-1108 ES82 5147 PTA-1109 ES83 5148 PTA-1110 ES84 5149 PTA-1111

TABLE 126 Library No. Clones es75 M00063947D:D01 es79 M00064003B:C10M00063158A:A01 M00064302A:D10 M00063517A:A04 M00064309C:H09M00063520D:E11 M00064310D:F03 M00063638C:G12 M00064322C:A10M00063642B:A08 M00064359B:H12 M00063686B:E07 M00064390A:C05M00063689D:E12 M00064404A:B05 M00063781B:B10 M00064404C:G05M00063826A:D03 M00064404D:A06 es76 M00063838B:G08 es80 M00064429D:B07M00063838B:G08 M00064446A:D11 M00063841A:B09 M00064457D:C09M00063886A:B06 M00064476D:C04 M00063910D:A12 M00064506A:C07M00063912A:D06 M00064514A:G10 M00063920D:H05 M00064520A:F08M00063928A:G09 M00064579D:E11 M00063934B:E04 M00064620C:D01M00063945A:C03 M00064624D:C09 es77 M00064032D:G04 es81 M00064633C:A03M00064046A:G02 M00064637B:F03 M00064053C:G04 M00064690A:C04M00064053D:F02 M00064690A:C04 M00064082A:A08 M00064714A:G03M00064089B:F09 M00064723D:H11 M00064132B:B07 GKC10154-1 M00064138A:F11GKC10154-3 M00064161B:G04 M00064175B:B09 es78 M00064178C:C04M00064179A:C04 M00064200D:E08 M00064248A:E02 M00064270B:B03M00064271B:D03 M00063580C:A06 M00063594B:H07 M00064002C:F06M00064002C:H09 es82 M00063151A:G06 M00063852D:F07 M00063151D:B10M00063888D:D05 M00063152C:B07 M00063888D:F02 M00063156D:H10M00063890A:F11 M00063158A:E11 M00063890A:H04 M00063158A:E11M00063891A:F11 M00063452A:F08 M00063892B:G02 M00063453B:F08M00063898A:A10 M00063462D:D07 M00063915C:E01 M00063463D:B05M00063919C:E07 M00063466C:C11 M00063920D:H02 M00063467D:H07M00063922B:A12 M00063478C:D01 M00063925B:F04 M00063482A:A08M00063926A:H04 M00063482A:F07 M00063931B:E10 M00063485A:E05M00063931B:F07 M00063487C:C02 M00063932D:G08 M00063514C:D03M00063934C:C10 M00063514C:E08 M00063938B:H07 M00063515B:F06M00063939C:D06 M00063515B:H02 M00063939C:H01 M00063518D:A01M00063940D:F09 M00063520D:D08 M00063940D:F09 M00063604A:B11M00063941B:C12 M00063606C:B04 M00063943B:G12 M00063610D:C11M00063949D:A05 M00063613D:C11 M00064021D:H01 M00063617D:F09M00064025D:E07 M00063627C:F06 M00064025D:H12 M00063636A:E01M00064033C:C11 M00063681B:C02 M00064033D:B01 M00063682A:C04M00063843B:D07 M00063685A:C02 M00063848C:G11 M00063774A:D09M00063852B:D08 M00063784A:H12 M00063818C:A09 M00063784C:E10M00063828A:H12 M00063785C:F03 M00063828D:E05 M00063795C:D09M00063839A:F01 M00063801B:D04 M00063841A:E08 M00063804C:A11M00063805D:E05 M00063807A:D12 M00063810C:E03 es83 M00064043D:C09M00063577C:C02 M00064048C:G12 M00063578B:E02 M00064053B:D09M00063578C:A06 M00064057C:H10 M00063580D:B06 M00064059A:C11M00063593A:D03 M00064060B:D03 M00063600C:C09 M00064079C:A10M00063955C:F07 M00064082D:D10 M00063955D:F05 M00064083D:E05M00063956A:F05 M00064086C:E01 M00063957A:E02 M00064090C:A02M00063957A:E02 M00064090D:D09 M00063967C:A12 M00064105B:A03M00063967D:G02 M00064106C:G03 M00063968D:G08 M00064113B:C04M00063972C:E10 M00064115B:E12 M00063978B:B06 M00064119B:H10M00063981D:A06 M00064119C:D12 M00063990A:D05 M00064122C:B06M00063990A:D05 M00064126C:C02 M00063997C:B12 M00064126C:F12M00063998C:E09 M00064136C:D12 M00064000B:C03 M00064144D:A07M00064001A:B03 M00064151B:C07 M00064005D:A08 M00064159A:H03M00064008A:B01 M00064165A:B12 M00064009A:C01 M00064171D:E05M00064014D:H05 M00064171D:E05 M00064018C:E07 M00064172C:A02M00064293D:B12 M00064173B:E01 M00064294D:F01 M00064176D:H10M00063557D:C07 M00064178B:A05 M00063559D:G03 M00064178B:A05M00063571B:G03 M00064180A:G03 M00063575B:G02 M00064186C:B03M00063555B:D01 M00064188B:G08 M00063533A:C12 M00064194C:D02M00063534C:A02 M00064212D:E04 M00063538D:B01 M00064260C:E05M00063539C:C11 M00064268D:G03 M00064272C:G01 M00063163A:G04M00063165A:C09 es84 M00064307B:G02 M00064564A:C02 M00064307C:G03M00064568A:H06 M00064310C:A10 M00064569B:A09 M00064328B:H04M00064569B:A09 M00064328B:H09 M00064571C:C04 M00064337D:F01M0064577C:B120 M00064341A:C02 M00064579A:C06 M00064345A:A03M00064593A:A05 M00064346C:B09 M00064593D:C01 M00064349D:H01M00064601C:G07 M00064352C:H01 M00064601D:B05 M00064354A:A10M00064605C:G05 M00064358A:G03 M00064610D:H01 M00064358C:D09M00064620D:G05 M00064375B:G07 M00064624C:B03 M00064376A:A05M00064631A:C07 M00064385D:C11 M00064631A:C07 M00064386B:C02M00064631C:H11 M00064386B:C02 M00064636B:A04 M00064393B:H04M00064649A:E04 M00064399A:E01 M00064650B:B07 M00064405B:C04M00064652B:D09 M00064406B:H06 M00064675C:E09 M00064414D:D06M00064678D:F05 M00064415B:G03 M00064693D:F08 M00064424B:C12M00064723C:H04 M00064428B:A12 M00064723D:H03 M00064447B:A07M00064723D:H03 M00064447B:C06 M00003773D:H02 M00064450C:E07M00021929A:D03 M00064452D:E11 M00043134A:A05 M00064454A:H10M00064534D:F06 M00064454C:B06 M00064550A:A07 M00064460C:B01M00064554D:A03 M00064467B:D06 M00064526D:F05 M00064481C:F03M00064527A:H07 M00064508A:B09 M00064530B:H02 M00064514D:F11M00064532D:G06 M00064517B:F04 M00064520A:E04 M00064517B:F10M00064520A:E04 M00064517C:F11 M00064524A:A09

TABLE 127 Table 8 Path Primary Primary Histo Incidence Regional DistantDescrip Patient Report Anatomical Tumor Tumor Path Local LymphnodeLymphnode Lymphnode Met Distant Dist Met ID ID Loc Size Grade GradeInvasion Met Met Grade & Loc Met Grade Comment 15 21 Ascending 4.0 T3 G2extending positive 3/8 N1 negative MX invasive colon intoadenocarcinoma, subserosal moderately adipose differentiated; tissuefocal perineural invasion is seen 52 71 Ascending 9.0 T3 G3 Invasionnegative  0/12 N0 negative M0 Hyper colon through plastic muscularispolyp propria, in subserosal appendix. involvement; ileocec. valveinvolvement 121 140 sigmoid 6 T4 G2 Invasion of negative  0/34 N0negative M0 Perineural muscularis invasion; propria into donut serosa,anastomosis involving negative. submucosa One of urinary tubulo bladdervillous and one tubular adenoma with no high grade dysplasia. 125 144Cecum 6 T3 G2 Invasion negative  0/19 N0 neagtive M0 patient through thehistory muscularis of propria into metastatic suserosal melanoma adiposetissue. Ileocecal junction. 128 147 Transverse 5.0 T3 G2 Invasion ofpositive 1/5 N1 negative M0 colon muscularis propria into percolonic fat130 149 Splenic 5.5 T3 through positive 10/24 N2 negative M1 flexurewall and into surrounding adipose tissue 133 152 Rectum 5.0 T3 G2Invasion negative 0/9 N0 negative M0 Small through separate muscularistubular propria into adenoma non- (0.4 cm) peritonealized pericolictissue; gross configuration is annular. 141 160 Cecum 5.5 T3 G2 Invasionof positive  7/21 N2 positive adenocarcinoma M1 Perineural muscularis(Liver) consistant invasion propria into with identified pericolonicprimary adjacent adipose to tissue, but metastatic not throughadenocarcinoma. serosa. Arising from tubular adenoma. 156 175 Hepatic3.8 T3 G2 Invasion positive  2/13 N1 negative M0 Separate flexurethrough tubolo mucsularis villous propria into and subserosa/pericolictubular adipose, adenomas no serosal involvement. Gross configurationannular. 228 247 Rectum 5.8 T3 G2 to Invasion positive 1/8 N1 negativeMX Hyper G3 through plastic muscularis polyps propria to involvesubserosal, perirectoal adipose, and serosa 264 283 Ascending 5.5 T3 G2Invasion negative  0/10 N0 negative M0 Tubul colon through ovillousmuscularis adenoma propria into with subserosal high adipose gradetissue. dysplasia 266 285 Transverse 9 T3 G2 Invades negative  0/15 N1positive 0.4 cm, MX colon through (Mesenteric may muscularis deposit)represent propria to lymphnode involve completely pericolonic replacedadipose, by extends to tumor serosa. 268 287 Cecum 6.5 T2 G2 Invadesfull negative  0/12 N0 negative M0 thickness of muscularis propria, butmesenteric adipose free of malignancy 278 297 Rectum 4 T3 G2 Invasionpositive  7/10 N2 negative M0 Descending into colon perirectal polyps,adipose no tissue. HGD or carcinoma identified.. 295 314 Ascending 5.0T3 G2 Invasion negative  0/12 N0 negative M0 Melanosis colon throughcoli muscularis and propria into diverticular percolic disease. adiposetissue. 339 358 Restosigmo 6 T3 G2 Extends negative 0/6 N0 negative M0 1id into hyperplastic perirectal polyp fat but identified does not reachserosa 341 360 Ascending 2 cm T3 G2 Invasion negative 0/4 N0 negative MXcolon invasive through muscularis propria to involve pericolonic fat.Arising from villous adenoma. 356 375 Sigmoid 6.5 T3 G2 Through negative0/4 N0 negative M0 colon wall into subserosal adipose tissue. No serosalspread seen. 360 412 Ascending 4.3 T3 G2 Invasion positive 1/5 N1negative M0 Two colon thru mucosal muscularis polyps propria topericolonic fat 392 444 Ascending 2 T3 G2 Invasion positive 1/6 N1positive Macro M1 Tumor colon through (Liver) vesicular arisingmuscularis and at propria into microvesicular prior subserosal steatosisileocolic adipose surgical tissue, not anastomosis. serosa. 393 445Cecum 6.0 T3 G2 Cecum, negative  0/21 N0 Negative M0 invades throughmuscularis propria to involve subserosal adipose tissue but not serosa.413 465 Ascending 4.8 T3 G2 Invasive negative 0/7 N0 positiveadenocarcinoma M1 rediagnosis colon through (Liver) in of muscularismultiple oophorectomy to involve slides path periserosal to fat;metastatic abutting colon ileocecal cancer. junction. 505 383 7.5 cm T3G2 Invasion positive  2/17 N1 positive moderately M1 Anatomical max dimthrough (Liver) differentiated location muscularis adenocarcinoma, ofpropria consistant report. involving with Evidence pericolic primar ofadipose, chronic serosal colitis. surface uninvolved 517 395 Sigmoid 3T3 G2 penetrates positive 6/6 N2 negative M0 No muscularis mentionpropria, of involves distant pericolonic met in fat. report 534 553Ascending 12 T3 G3 Invasion negative 0/8 N0 negative M0 Omentum colonthrough the with muscularis fibrosis propria and involving fat pencolicnecrosis. fat. Serosa Small free of bowel tumor. with acute and chronicserositis, focal abscess and adhesion. 546 565 Ascending 5.5 T3 G2Invasion positive  6/12 N2 positive metastatic M1 colon through (Liver)adenocarcinoma muscularis propria extensively through submucosal andextending to serosa. 577 596 Cecum 11.5 T3 G2 Invasion negative  0/58 N0negative M0 Appendix through the dilated bowel wall, and into fibrotic,suberosal but adipose. not Serosal involved surface free by of tumor.tumor 695 714 Cecum 14 T3 G2 extending negative  0/22 N0 negative MXtubular through adenoma bowel wall and into serosalfat hyperplsticpolypspresent, moderately differentiated adenoma with mucinousdiferentiation (% not stated) 784 803 Ascending 3.5 T3 G3 throughpositive  5/17 N2 positive M1 invasive colon muscularis (Liver) poorlypropria into differentiated pericolic adenosquamous soft tissuescarcinoma 786 805 Descending 9.5 T3 G2 through negative  0/12 N0positive M1 moderately colon muscularis (Liver) differentiated propriainto invasive pericolic adenocarcinoma fat, but not at serosal surface791 810 Ascending 5.8 T3 G3 through the positive 13/25 N2 positive M1poorly colon muscularis (Liver) differentiated propria into invasivepericolic fat colonic adenocarcinoma 888 908 Ascending 2.0 T2 G1 intopositive  3/21 N0 positive M1 well- colon muscularis (Liver) to propriamoderately- differentiated adenocarcinoma; this patient has tumors ofthe ascending colon and the sigmoid colon 889 909 Cecum 4.8 T3 G2through positive 1/4 N1 positive M1 moderately muscularis (Liver)differentiated propria int adenocarcinoma subserosal tissue

The deposits described herein are provided merely as convenience tothose of skill in the art, and is not an admission that a deposit isrequired under 35 U.S.C. §112. The sequence of the polynucleotidescontained within the deposited material, as well as the amino acidsequence of the polypeptides encoded thereby, are incorporated herein byreference and are controlling in the event of any conflict with thewritten description of sequences herein. A license may be required tomake, use, or sell the deposited material, and no such license isgranted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones. Where theATCC deposit is composed of a pool of cDNA clones or a library of cDNAclones, the deposit was prepared by first transfecting each of theclones into separate bacterial cells. The clones in the pool or librarywere then deposited as a pool of equal mixtures in the compositedeposit. Particular clones can be obtained from the composite depositusing methods well known in the art. For example, a bacterial cellcontaining a particular clone can be identified by isolating singlecolonies, and identifying colonies containing the specific clone throughstandard colony hybridization techniques, using an oligonucleotide probeor probes designed to specifically hybridize to a sequence of the cloneinsert (e.g., a probe based upon unmasked sequence of the encodedpolynucleotide having the indicated SEQ ID NO). The probe should bedesigned to have a T_(m) of approximately 80° C. (assuming 2° C. foreach A or T and 4° C. for each G or C). Positive colonies can then bepicked, grown in culture, and the recombinant clone isolated.Alternatively, probes designed in this manner can be used to PCR toisolate a nucleic acid molecule from the pooled clones according tomethods well known in the art, e.g., by purifying the cDNA from thedeposited culture pool, and using the probes in PCR reactions to producean amplified product having the corresponding desired polynucleotidesequence.

Those skilled in the art will recognize, or be able to ascertain, usingnot more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such specific embodimentsand equivalents are intended to be encompassed by the following claims.

Example 82 Source of Biological Materials and Overview of NovelPolynucleotides Expressed by the Biological Materials

Candidate polynucleotides that may represent novel polynucleotides wereobtained from cDNA libraries generated from selected cell lines andpatient tissues. In order to obtain the candidate polynucleotides, mRNAwas isolated from several selected cell lines and patient tissues, andused to construct cDNA libraries. The cells and tissues that served assources for these cDNA libraries are summarized in Table 129 below.

Human colon cancer cell line Km12L4-A (Morikawa, et al., Cancer Research(1988) 48:6863) is derived from the KM12C cell line. The KM12C cell line(Morikawa et al. Cancer Res. (1988) 48:1943-1948), which is poorlymetastatic (low metastatic) was established in culture from a Dukes'stage B2 surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863).The KM12L4-A is a highly metastatic subline derived from KM12C (Yeatmanet al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu.Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C andKM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) arewell-recognized in the art as a model cell line for the study of coloncancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. CancerRes. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin.Exp. Metastasis (1996) 14:246).

The MDA-MB-231 cell line (Brinkley et al. Cancer Res. (1980)40:3118-3129) was originally isolated from pleural effusions (Cailleau,J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential,and forms poorly differentiated adenocarcinoma grade II in nude miceconsistent with breast carcinoma. The MCF7 cell line was derived from apleural effusion of a breast adenocarcinoma and is non-metastatic. TheMV-522 cell line is derived from a human lung carcinoma and is of highmetastatic potential. The UCP-3 cell line is a low metastatic human lungcarcinoma cell line; the MV-522 is a high metastatic variant of UCP-3.These cell lines are well-recognized in the art as models for the studyof human breast and lung cancer (see, e.g., Chandrasekaran et al.,Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J MedChem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer(1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res(1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987)40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 andUCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner etal., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., AnticancerDrugs (1997) 8:696 (MV522)).

The samples of libraries 15-20 are derived from two different patients(UC#2, and UC#3). The bFGF-treated HMVEC were prepared by incubationwith bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMVEC were prepared byincubation with 20 ng/ml VEGF for 2 hrs. Following incubation with therespective growth factor, the cells were washed and lysis buffer addedfor RNA preparation. The GRRpz and WOca cell lines were provided by Dr.Donna M. Peehl, Department of Medicine, Stanford University School ofMedicine. GRRpz was derived from normal prostate epithelium. The WOcacell line is a Gleason Grade 4 cell line. TABLE 129 Description of cDNALibraries Number Library of Clones (lib #) Description in Library 0Artificial library composed of deselected clones (clones with no 673associated variant or cluster) 1 Human Colon Cell Line Km12 L4: HighMetastatic Potential 308731 (derived from Km12C) 2 Human Colon Cell LineKm12C: Low Metastatic Potential 284771 3 Human Breast Cancer Cell LineMDA-MB-231: High Metastatic 326937 Potential; micro-mets in lung 4 HumanBreast Cancer Cell Line MCF7: Non Metastatic 318979 8 Human Lung CancerCell Line MV-522: High Metastatic Potential 223620 9 Human Lung CancerCell Line UCP-3: Low Metastatic Potential 312503 12 Human microvascularendothelial cells (HMEC) - UNTREATED 41938 (PCR (OligodT) cDNA library)13 Human microvascular endothelial cells (HMEC) - bFGF TREATED 42100(PCR (OligodT) cDNA library) 14 Human microvascular endothelial cells(HMEC) - VEGF TREATED 42825 (PCR (OligodT) cDNA library) 15 NormalColon - UC#2 Patient (MICRODISSECTED PCR (OligodT) 282722 cDNA library)16 Colon Tumor - UC#2 Patient (MICRODISSECTED PCR (OligodT) 298831 cDNAlibrary) 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467(MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3Patient (MICRODISSECTED PCR (OligodT) 36216 cDNA library) 19 ColonTumor - UC#3 Patient (MICRODISSECTED PCR (OligodT) 41388 cDNA library)20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956(MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived fromnormal prostate epithelium 164801 22 WOca Cells derived from GleasonGrade 4 prostate cancer 162088 epithelium 23 Normal Lung Epithelium ofPatient #1006 (MICRODISSECTED 306198 PCR (OligodT) cDNA library) 24Primary tumor, Large Cell Carcinoma of Patient #1006 309349(MICRODISSECTED PCR (OligodT) cDNA library) 25 Normal ProstateEpithelium from Patient IF97-26811 279444 26 Prostate Cancer EpitheliumGleason 3 + 3 Patient IF97-26811 269406 27 Normal Breast Epithelium fromPatient 515 239494 28 Primary Breast tumor from Patient 515 259960 29Lymph node metastasis from Patient 515 326786 30 Normal ProstateEpithelium from Chiron Patient ID 884 298431 31 Prostate CancerEpithelium (Gleason 4 + 4) from Chiron Patient ID 331941 884

Characterization of Sequences in the Libraries

After using the software program Phred (ver 0.000925.c, Green and Weing,©1993-2000) to select those polynucleotides having the best qualitysequence, the polynucleotides were compared against the public databasesto identify any homolgous sequences. The sequences of the isolatedpolynucleotides were first masked to eliminate low complexity sequencesusing the BLASTX masking program (Claverie “Effective Large-ScaleSequence Similarity Searches,” In: Computer Methods for MacromolecularSequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 AcademicPress, NY, N.Y. (1996); see particularly Claverie, in “Automated DNASequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993)17:191). Generally, masking does not influence the final search results,except to eliminate sequences of relatively little interest due to theirlow complexity, and to eliminate multiple “hits” based on similarity torepetitive regions common to multiple sequences, e.g., Alu repeats. Theremaining sequences were then used in a BLASTN vs. GenBank search;sequences that exhibited greater than 70% overlap, 99% identity, and a pvalue of less than 1×10e−40 were discarded. Sequences from this searchalso were discarded if the inclusive parameters were met, but thesequence was ribosomal or vector-derived.

The resulting sequences from the previous search were classified intothree groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP(non-redundant proteins) database search: (1) unknown (no hits in theGenBank search), (2) weak similarity (greater than 45% identity and pvalue of less than 1×10e−5), and (3) high similarity (greater than 60%overlap, greater than 80% identity, and p value less than 1×10e−5).Sequences having greater than 70% overlap, greater than 99% identity,and p value of less than 1×10e−40 were discarded.

The remaining sequences were classified as unknown (no hits), weaksimilarity, and high similarity (parameters as above). Two searches wereperformed on these sequences. First, a BLAST vs. EST database search wasperformed and sequences with greater than 99% overlap, greater than 99%similarity and a p value of less than 1×10e−40 were discarded. Sequenceswith a p value of less than 1×10e−65 when compared to a databasesequence of human origin were also excluded. Second, a BLASTN vs. PatentGeneSeq database was performed and sequences having greater than 99%identity, p value less than 1×10e−40, and greater than 99% overlap werediscarded.

The remaining sequences were subjected to screening using other rulesand redundancies in the dataset. Sequences with a p value of less than1×10e−111 in relation to a database sequence of human origin werespecifically excluded. The final result provided the 8064 sequenceslisted as SEQ ID NOS 15991-22000 in the accompanying Sequence Listingand summarized in Table 130 (inserted prior to claims). Each identifiedpolynucleotide represents sequence from at least a partial mRNAtranscript.

Summary of Polynucleotides of the Invention

Table 130 (inserted prior to claims) provides a summary ofpolynucleotides isolated as described. Specifically, Table 130provides: 1) the SEQ ID NO (“SEQ ID”) assigned to each sequence for usein the present specification; 2) the Cluster Identification No.(“CLUSTER”); 3) the Sequence Name assigned to each sequence; 3) thesequence name (“SEQ NAME”) used as an internal identifier of thesequence; 4) the orientation of the sequence (“ORIENT”) (either forward(F) or reverse (R)); 5) the name assigned to the clone from which thesequence was isolated (“CLONE ID”); and the name of the library fromwhich the sequence was isolated (“LIBRARY”), where the notatiionindicates that name of the cell line or patient sample (e.g.,UC2-NormColon indicates the sequence was isolated from normla colontissue of the patient assigned the idnetification UC#2). Because atleast some of the provided polynucleotides represent partial mRNAtranscripts, two or more polynucleotides may represent different regionsof the same mRNA transcript and the same gene and/or may be containedwithin the same clone. Thus, for example, if two or more SEQ ID NOS: areidentified as belonging to the same clone, then either sequence can beused to obtain the full-length mRNA or gene

Example 83 Results of Public Database Search to Identify Function ofGene Products

SEQ ID NOS: 15991-22000 were translated in all three reading frames, andthe nucleotide sequences and translated amino acid sequences used asquery sequences to search for homologous sequences in either the GenBank(nucleotide sequences) or Non-Redundant Protein (amino acid sequences)databases. Query and individual sequences were aligned using the BLAST2.0 programs, available over the world wide at a site sponsored by theNational Center for Biotechnology Information, which is supported by theNational Library of Medicine and the National Institutes of Health (seealso Altschul, et al. Nucleic Acids Res. (1997) 25:3389-3402). Thesequences were masked to various extents to prevent searching ofrepetitive sequences or poly-A sequences, using the BLASTX program formasking low complexity as described above in Example 82.

Tables 131A and 131B (inserted prior to claims) provides the alignmentsummaries having a p value of 1×10e−2 or less indicating substantialhomology between the sequences of the present invention and those of theindicated public databases. Specifically, Table 131A provides the SEQ IDNO of the query sequence, the accession number of the GenBank databaseentry of the homologous sequence, and the individual p value of eachalignment. Table 131A provides the SEQ ID NO of the query sequence, theaccession number of the Non-Redundant Protein database entry of thehomologous sequence, and the individual p value of each alignment. Thealignments provided in Tables 131A and 131B are the best availablealignment to a DNA or amino acid sequence at a time just prior to filingof the present specification. The activity of the polypeptide encoded bythe SEQ ID NOS listed in these tables can be extrapolated to besubstantially the same or substantially similar to the activity of thereported nearest neighbor or closely related sequence. The accessionnumber of the nearest neighbor is reported, providing a publiclyavailable reference to the activities and functions exhibited by thenearest neighbor. The public information regarding the activities andfunctions of each of the nearest neighbor sequences is incorporated byreference in this application. Also incorporated by reference is allpublicly available information regarding the sequence, as well as theputative and actual activities and functions of the nearest neighborsequences listed in Tables 131A and 131B and their related sequences.The search program and database used for the alignment, as well as thecalculation of the p value are also indicated.

Full length sequences or fragments of the polynucleotide sequences ofthe nearest neighbors can be used as probes and primers to identify andisolate the full length sequence of the corresponding polynucleotide.The nearest neighbors can indicate a tissue or cell type to be used toconstruct a library for the full-length sequences of the correspondingpolynucleotides.

Example 83.5 Members of Protein Families

SEQ ID NOS:15991-22000 were used to conduct a profile search asdescribed in the specification above. Several of the polynucleotides ofthe invention were found to encode polypeptides having characteristicsof a polypeptide belonging to a known protein family (and thus representmembers of these protein families) and/or comprising a known functionaldomain. Table 132 (inserted before claims) provides the SEQ ID NO: ofthe query sequence, the Sequence Name, the Cluster to which the sequenceis assigned, a brief description of the profile hit, the orientation(Direction, “Dir”) of the query sequence with respect to the individualsequence) where forward (for) indicates that the alignment is in thesame direction (left to right) as the sequence provided in the SequenceListing and reverse (rev) indicates that the alignment is with asequence complementary to the sequence provided in the SequenceListing), and the score of the profile hit.

Some polynucleotides exhibited multiple profile hits where the querysequence contains overlapping profile regions, and/or where the sequencecontains two different functional domains. Each of the profile hits ofTable 132 is described in more detail below. The acronyms for theprofiles (provided in parentheses) are those used to identify theprofile in the Pfam, Prosite, and InterPro databases. The Pfam databasecan be accessed through web sites supported by Genome Sequencing Centerat the Washington University School of Medicine or by the EuropeanMolecular Biology Laboratories in Heidelberg, Germany. The Prositedatabase can be accessed at the ExPASy Molecular Biology Server on theinternet. The InterPro database can be accessed at a web site supportedby the EMBL European Bioinformatics Institute. The public informationavailable on the Pfam, Prosite, and InterPro databases regarding thevarious profiles, including but not limited to the activities, function,and consensus sequences of various proteins families and proteindomains, is incorporated herein by reference. Table 132 SEQ ID NO SEQNAME CLUSTER PROFILE NAME DIR SCORE 15996 2102.B18.gz43_275316 558147Ets_Cterm for 19.58 15999 2103.M06.gz43_275519 377696 protkinase for20.71 16028 2153.K14.gz43_278937 372952 Dead_box_helic for 172.21 160292154.M04.gz43_279163 377696 protkinase for 20.71 160512165.H06.gz43_280342 393635 zf-c2h2 for 33.96 16059 2166.J11.gz43_281368377696 protkinase for 20.71 16098 2118.A09.gz43_307025 446397 bzip for19.15 16107 2131.I13.gz43_308085 34071 wd40 for 37.45 161082131.B14.gz43_308094 221686 protkinase for 33.14 162181573.F18.gz43_208848 639849 PH for 42.77 16219 1573.K19.gz43_208869486238 protkinase rev 45.41 16405 1585.G22.gz43_210545 412416Dead_box_helic for 49.67 16435 1587.B06.gz43_211440 446984 ANK rev 23.1216476 1597.G06.gz43_212233 639593 defensins rev 18.27 164771597.J06.gz43_212236 557975 ANK for 35.63 16492 1597.F18.gz43_212424596882 zf-c2h2 rev 18.13 16690 1694.M19.gz43_214375 425923 zf-c2h2 for32.76 16837 1706.P07.gz43_216138 639901 zf-c2h2 for 19.43 168671707.J02.gz43_216453 550237 zf-ccch for 26.74 17501 1755.P24.gz43_223395606129 rvt for 37.6 17704 1790.C14.gz43_226997 727150 bzip for 24.218024 1828.J19.gz43_232472 728303 zf-c2h2 rev 18.19 180281828.P21.gz43_232510 509678 Retvir_asp_protease for 28.5 180441838.N05.gz43_233020 481614 zf-c2h2 for 18.52 18504 1888.O06.gz43_240269451764 rvt for 49.99 18963 1924.H18.gz43_245579 499700 7tm_1 rev 73.719003 1935.E18.gz43_246500 490805 ANK rev 28.74 191301981.O19.gz43_248062 558949 zf-c3hc4 rev 19.16 193931958.N12.gz43_250647 556308 zf-c2h2 for 40.77 19514 1923.M22.gz43_252963562603 zf-c2h2 rev 42.42 19643 1995.C03.gz43_256117 562152 zf-c2h2 rev18.97 19679 1995.P13.gz43_256290 562989 EGF rev 19.4 197131995.B24.gz43_256452 556632 zf-c2h2 rev 20.64 19804 2007.F09.gz43_257778560652 zf-c2hc rev 21.49 19921 2008.F18.gz43_258308 550497 bzip for20.27 20141 1669.G11.gz43_260853 503275 protkinase rev 43.25 203461682.O17.gz43_262495 450211 bzip rev 26.06 20363 1682.F21.gz43_262550546740 EFhand rev 18.72 20678 2018.K14.gz43_264760 432970 zf-c2h2 for48.43 20969 2041.C09.gz43_266976 556632 zf-c2h2 rev 20.88 214572067.I20.gz43_271090 551617 7tm_1 rev 19.77 21498 2068.F14.gz43_271375561707 7tm_1 rev 24.27 21512 2068.D17.gz43_271421 554774 tgf-beta for18.24 21746 2176.J17.gz43_281945 412416 Dead_box_helic for 37.64 219911561.C22.gz43_314731 447072 PH for 31.95

Example 84 Description of Libraries and Detection of DifferentialExpression

The relative expression levels of the polynucleotides of the inventionwere assessed in several libraries prepared from various sources,including cell lines and patient tissue samples. Table 129 aboveprovides a summary of these libraries, including the shortened libraryname, the mRNA source used to prepared the cDNA library, the “nickname”of the library that is used in the tables below (in quotes), and theapproximate number of clones in the library.

Each of the libraries is composed of a collection of cDNA clones that inturn are representative of the mRNAs expressed in the indicated mRNAsource. In order to facilitate the analysis of the millions of sequencesin each library, the sequences were assigned to clusters. The concept of“cluster of clones” is derived from a sorting/grouping of cDNA clonesbased on their hybridization pattern to a panel of roughly 300 7 bpoligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29).Random cDNA clones from a tissue library are hybridized at moderatestringency to 300 7 bp oligonucleotides. Each oligonucleotide has somemeasure of specific hybridization to that specific clone. Thecombination of 300 of these measures of hybridization for 300 probesequals the “hybridization signature” for a specific clone. Clones withsimilar sequence will have similar hybridization signatures. Bydeveloping a sorting/grouping algorithm to analyze these signatures,groups of clones in a library can be identified and brought togethercomputationally. These groups of clones are termed “clusters”. Dependingon the stringency of the selection in the algorithm (similar to thestringency of hybridization in a classic library cDNA screeningprotocol), the “purity” of each cluster can be controlled. For example,artifacts of clustering may occur in computational clustering just asartifacts can occur in “wet-lab” screening of a cDNA library with 400 bpcDNA fragments, at even the highest stringency. The stringency used inthe implementation of cluster herein provides groups of clones that arein general from the same cDNA or closely related cDNAs. Closely relatedclones can be a result of different length clones of the same cDNA,closely related clones from highly related gene families, or splicevariants of the same cDNA.

Differential expression for a selected cluster was assessed by firstdetermining the number of cDNA clones corresponding to the selectedcluster in the first library (Clones in 1^(st)), and the determining thenumber of cDNA clones corresponding to the selected cluster in thesecond library (Clones in 2^(nd)). Differential expression of theselected cluster in the first library relative to the second library isexpressed as a “ratio” of percent expression between the two libraries.In general, the “ratio” is calculated by: 1) calculating the percentexpression of the selected cluster in the first library by dividing thenumber of clones corresponding to a selected cluster in the firstlibrary by the total number of clones analyzed from the first library;2) calculating the percent expression of the selected cluster in, thesecond library by dividing the number of clones corresponding to aselected cluster in a second library by the total number of clonesanalyzed from the second library; 3) dividing the calculated percentexpression from the first library by the calculated percent expressionfrom the second library. If the “number of clones” corresponding to aselected cluster in a library is zero, the value is set at 1 to aid incalculation. The formula used in calculating the ratio takes intoaccount the “depth” of each of the libraries being compared, i.e., thetotal number of clones analyzed in each library.

In general, a polynucleotide is significantly differentially expressedbetween two samples when the ratio value is greater than at least about2, preferably greater than at least about 3, more preferably greaterthan at least about 5, where the ratio value is calculated using themethod described above. The significance of differential expression isdetermined using a z score test (Zar, Biostatistical Analysis, PrenticeHall, Inc., USA, “Differences Between Proportions,” pp 296-298 (1974).

Using this approach, a number of polynucleotide sequences wereidentified as being differentially expressed between, for example, cellsderived from high metastatic potential cancer tissue and low metastaticcancer cells, and between cells derived from metastatic cancer tissueand normal tissue. Evaluation of the levels of expression of the genescorresponding to these sequences can be valuable in diagnosis,prognosis, and/or treatment (e.g., to facilitate rationale design oftherapy, monitoring during and after therapy, etc.). Moreover, the genescorresponding to differentially expressed sequences described herein canbe therapeutic targets due to their involvement in regulation (e.g.,inhibition or promotion) of development of, for example, the metastaticphenotype. For example, sequences that correspond to genes that areincreased in expression in high metastatic potential cells relative tonormal or non-metastatic tumor cells may encode genes or regulatorysequences involved in processes such as angiogenesis, differentiation,cell replication, and metastasis.

Detection of the relative expression levels of differentially expressedpolynucleotides described herein can provide valuable information toguide the clinician in the choice of therapy. For example, a patientsample exhibiting an expression level of one or more of thesepolynucleotides that corresponds to a gene that is increased inexpression in metastatic or high metastatic potential cells may warrantmore aggressive treatment for the patient. In contrast, detection ofexpression levels of a polynucleotide sequence that corresponds toexpression levels associated with that of low metastatic potential cellsmay warrant a more positive prognosis than the gross pathology wouldsuggest.

A number of polynucleotide sequences of the present invention aredifferentially expressed between human microvascular endothelial cells(HMVEC) that have been treated with growth factors relative to untreatedHMVEC. Sequences that are differentially expressed between growthfactor-treated HMVEC and untreated HMVEC can represent sequencesencoding gene products involved in angiogenesis, metastasis (cellmigration), and other development and oncogenic processes. For example,sequences that are more highly expressed in HMVEC treated with growthfactors (such as bFGF or VEGF) relative to untreated HMVEC can serve asdrug targets for chemotherapeutics, e.g., decreasing expression of suchup-regulated genes or inhibiting the activity of the encoded geneproduct would serve to inhibit tumor cell angiogenesis. Detection ofexpression of these sequences in colon cancer tissue can be valuable indetermining diagnostic, prognostic and/or treatment informationassociated with the prevention of achieving the malignant state in thesetissues, and can be important in risk assessment for a patient. Apatient sample displaying an increased level of one or more of thesepolynucleotides may thus warrant closer attention or more frequentscreening procedures to catch the malignant state as early as possible.

The differential expression of the polynucleotides can thus be used as,for example, diagnostic and/or prognostic markers, for risk assessment,patient treatment and the like. These polynucleotides can also be usedin combination with other molecular and/or biochemical markers.

The differential expression data for polynucleotides of the inventionthat have been identified as being differentially expressed acrossvarious combinations of the libraries described above is summarized inTable 133 (inserted prior to the claims). Table 133 provides: 1) theSequence Identification Number (“SEQ ID NO”) assigned to thepolynucleotide; 2) the cluster (“CLUSTER”) to which the polynucleotidehas been assigned as described above; 3) the library comparisons thatresulted in identifcation of the polynucleotide as being differentiallyexpressed (“PAIR AB”), where the cDNA libraries used are referenced bytheir library numbers; 4) the number of clones corresponding to thepolynucleotide in the first library listed (“CLONES A”); 5) the numberof clones corresponding to the polynucleotide in the second librarylisted (“CLONES B”); 6) the “RATIO PLUS” where the comparison resultedin a finding that the number of clones in library A is greater than thenumber of clones in library B; and 7) the “RATIO MINUS” where thecomparison resulted in a finding that the number of clones in library Bis greater than the number of clones in library A.

Detection of expression of genes that correspond to the abovepolynucleotides may be of particular interest in diagnosis, prognosis,risk assessment, and monitoring of treatment. Furthermore, differentialexpression of a specific gene across multiple libraries can also beindicative of a gene whose expression is associated with, for example,suppression of the metastatic phenotype or with development of the celltoward a metastatic phenotype. For example, SEQ ID NO:19734 correspondsto a gene that is expressed at relatively higher levels in metastatizedcolon tumor than in normal colon tissue. Thus a relatively increasedlevel of expression of the gene corresponding to SEQ ID NO: 19734 may beused as marker of a metastatic or pre-metastatic colon cels either aloneor in combination with other markers.

Some polynucleotides exhibited similar differential expression trends inlibraries of different tissue origin (see, e.g., SEQ ID NO:17327). Thesedata suggest that the differential expression patterns of some genesassociated with development of tumors indicate a role for those genesthat is non-specific to the tissue of origin.

Example 85 Detection of Differential Expression Using Arrays

mRNA isolated from samples of cancerous and normal colon tissue obtainedfrom patients were analyzed to identify genes differentially expressedin cancerous and normal cells. Normal and cancerous cells collected fromcryopreserved patient tissues were isolated using laser capturemicrodissection (LCM) techniques, which techniques are well known in theart (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran etal. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999)Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6;Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al.(1996) Science 274:998-1001).

Table 134 (inserted before the claims) provides information about eachpatient from which colon tissue samples were isolated, including: thePatient ID (“PT ID”) and Path ReportID (}Path ID”), which are numbersassigned to the patient and the pathology reports for identificationpurposes; the group (“Grp”) to which the patients have been assigned;the anatomical location of the tumor (“Anatom Loc”); the primary tumorsize (“Size”); the primary tumor grade (“Grade”); the identification ofthe histopathological grade (“Histo Grade”); a description of localsites to which the tumor had invaded (“Local Invasion”); the presence oflymph node metastases (“LN Met”); the incidence of lymph node metastases(provided as a number of lymph nodes positive for metastasis over thenumber of lymph nodes examined) (“Incidence Lymphnode Met”); the“Regional Lymphnode Grade”; the identification or detection ofmetastases to sites distant to the tumor and their location (“Dist Met &Loc”); the grade of distant metastasis (“Dist Met Grade”); and generalcomments about the patient or the tumor (“Comments”). Histophatology ofall primary tumors incidated the tumor was adenocarcinmoa except forPatient ID Nos. 130 (for which no information was provided), 392 (inwhich greater than 50% of the cells were mucinous carcinoma), and 784(adenosquamous carcinoma). Extranodal extensions were described in threepatients, Patient ID Nos. 784, 789, and 791. Lymphovascular invasion wasdescribed in Patient ID Nos. 128, 278, 517, 534, 784, 786, 789, 791,890, and 892. Crohn's-like infiltrates were described in seven patients,Patient ID Nos. 52, 264, 268, 392, 393, 784, and 791. Table 135 (below)provides information about the patients from whom the prostate tissuewas isolated. TABLE 135 Prostate paitent data. Prostate Patient ID TumorGleason Grade Normal Prostate Description 96 3 + 3 Adenocarcinoma Normalprostate; Benign hyperplasia 282 4 + 3 Adenocarcinoma Normal prostate;Benign hyperplasia 286 3 + 3 Adenocarcinoma Normal prostate; Benignhyperplasia 294 3 + 4 Adenocarcinoma Normal prostate; Benign hyperplasia362 3 + 3 Adenocarcinoma Normal prostate; Benign hyperplasia 428 4 + 3Adenocarcinoma Normal prostate; Benign hyperplasia 492 3 + 3Adenocarcinoma Normal prostate; Benign hyperplasia 492 3 + 3Adenocarcinoma Normal prostate; Benign hyperplasia 493 3 + 4Adenocarcinoma Normal prostate; Benign hyperplasia 510 3 + 3Adenocarcinoma Normal Prostate; Benign hyperplasia

Identification of Differentially Expressed Genes

cDNA probes were prepared from total RNA isolated from the patient cellsdescribed above. Since LCM provides for the isolation of specific celltypes to provide a substantially homogenous cell sample, this providedfor a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primercontaining a T7 RNA polymerase promoter, followed by second strand DNAsynthesis. cDNA was then transcribed in vitro to produce antisense RNAusing the T7 promoter-mediated expression (see, e.g., Luo et al. (1999)Nature Med 5:117-122), and the antisense RNA was then converted intocDNA. The second set of cDNAs were again transcribed in vitro, using theT7 promoter, to provide antisense RNA. Optionally, the RNA was againconverted into cDNA, allowing for up to a third round of T7-mediatedamplification to produce more antisense RNA. Thus the procedure providedfor two or three rounds of in vitro transcription to produce the finalRNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to theantisense RNA mix, and producing fluorescently labeled cDNA from the RNAstarting material. Fluorescently labeled cDNAs prepared from the tumorRNA sample were compared to fluorescently labeled cDNAs prepared fromnormal cell RNA sample. For example, the cDNA probes from the normalcells were labeled with Cy3 fluorescent dye (green) and the cDNA probesprepared from the tumor cells were labeled with Cy5 fluorescent dye(red), and vice versa.

Each array used had an identical spatial layout and control spot set.Each microarray was divided into two areas, each area having an arraywith, on each half, twelve groupings of 32×12 spots, for a total ofabout 9,216 spots on each array. The two areas are spotted identicallywhich provide for at least two duplicates of each clone per array.

Polynucleotides for use on the arrays were obtained from both publiclyavailable sources and from cDNA libraries generated from selected celllines and patient tissues. PCR products of from about 0.5 kb to 2.0 kbamplified from these sources were spotted onto the array using aMolecular Dynamics Gen III spotter according to the manufacturer'srecommendations. For polynucleotides described herein, the microarrayspot contained a clone having a cDNA from which the sequence wasderived. The first row of each of the 24 regions on the array had about32 control spots, including 4 negative control spots and 8 testpolynucleotides. The test polynucleotides were spiked into each samplebefore the labeling reaction with a range of concentrations from 2-600pg/slide and ratios of 1:1. For each array design, two slides werehybridized with the test samples reverse-labeled in the labelingreaction. This provided for about four duplicate measurements for eachclone, two of one color and two of the other, for each sample.

Table 136 (inserted before the claims) describes sequences present onthe arrays. Table 136 includes: 1) athe SEQ ID NO of the sequence of thepolynucleotide; and 2) the Spot ID, which is a unique identifier foreach spot ontaining target sequence of interest on all arrays used.

The differential expression assay was performed by mixing equal amountsof probes from tumor cells and normal cells of the same patient. Thearrays were prehybridized by incubation for about 2 hrs at 60° C. in5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twicein isopropanol. Following prehybridization of the array, the probemixture was then hybridized to the array under conditions of highstringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS.After hybridization, the array was washed at 55° C. three times asfollows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2%SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using aMolecular Dynamics Generation III dual color laser-scanner/detector. Theimages were processed using BioDiscovery Autogene software, and the datafrom each scan set normalized to provide for a ratio of expressionrelative to normal. Data from the microarray experiments was analyzedaccording to the algorithms described in U.S. application Ser. No.60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M.Randazzo, and entitled “Precision and accuracy in cDNA microarray data,”which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with theopposite color in order to perform the assay in both “color directions.”Each experiment was sometimes repeated with two more slides (one in eachcolor direction). The level fluorescence for each sequence on the arrayexpressed as a ratio of the geometric mean of 8 replicate spots/genesfrom the four arrays or 4 replicate spots/gene from 2 arrays or someother permutation. The data were normalized using the spiked positivecontrols present in each duplicated area, and the precision of thisnormalization was included in the final determination of thesignificance of each differential. The fluorescent intensity of eachspot was also compared to the negative controls in each duplicated areato determine which spots have detected significant expression levels ineach sample.

A statistical analysis of the fluorescent intensities was applied toeach set of duplicate spots to assess the precision and significance ofeach differential measurement, resulting in a p-value testing the nullhypothesis that there is no differential in the expression level betweenthe tumor and normal samples of each patient. During initial analysis ofthe microarrays, the hypothesis was accepted if p>10⁻³, and thedifferential ratio was set to 1.000 for those spots. All other spotshave a significant difference in expression between the tumor and normalsample. If the tumor sample has detectable expression and the normaldoes not, the ratio is truncated at 1000 since the value for expressionin the normal sample would be zero, and the ratio would not be amathematically useful value (e.g., infinity). If the normal sample hasdetectable expression and the tumor does not, the ratio is truncated to0.001, since the value for expression in the tumor sample would be zeroand the ratio would not be a mathematically useful value. These lattertwo situations are referred to herein as “on/off.” Database tables werepopulated using a 95% confidence level (p>0.05).

Table 136 (inserted before the claims) provides the results for geneproducts differentially expressed in the colon tumor samples relative tonormal tissue samples. Table 136 includes: 1) the SEQ ID NO; 2) the spotidentification number (“SpotID”); 3) the percentage of patients testedin which expression levels of the gene (as detected using thecorreponding clone) was at least 2-fold greater in cancerous colontissue (primary colon tumor) than in matched normal tissue(“Colon>2×T/N”); 4) the percentage of patients tested in whichexpression levels of the gene was less than or equal to one-half of theexpression level in matched normal cells (“Colon <=halfx T/N”); and 5)the colon number ratios, indicating the number of patients upon whichthe provided ratios was based. TABLE 136 SEQ ID T/N Colon T/N Colon T/NColon Num NO SpotID >2x <halfx Ratios 15996 43971 0.0 75.0 8.0 1602140453 0.0 42.9 7.0 16030 40457 0.0 71.4 7.0 16034 46308 0.0 50.0 8.016040 45610 0.0 62.5 8.0 16060 42816 0.0 50.0 8.0 16062 44673 0.0 50.08.0 16064 42422 0.0 37.5 8.0 16067 43983 0.0 37.5 8.0 16071 44679 0.050.0 8.0 16074 42418 0.0 37.5 8.0 16123 39755 0.0 42.9 7.0 16129 449160.0 50.0 8.0 16137 45618 0.0 37.5 8.0 16139 44926 0.0 50.0 8.0 1614244216 0.0 37.5 8.0 16143 38367 0.0 42.9 7.0 16148 38357 0.0 57.1 7.016151 41869 0.0 42.9 7.0 16152 43508 0.0 37.5 8.0 16154 38365 0.0 57.17.0 16156 39069 0.0 42.9 7.0 16161 39061 0.0 57.1 7.0 16170 39767 0.042.9 7.0 16174 43881 0.0 37.5 8.0 16176 43873 0.0 37.5 8.0 16185 397690.0 57.1 7.0 16186 39775 0.0 57.1 7.0 16187 46330 0.0 37.5 8.0 1618842471 0.0 37.5 8.0 16190 41173 0.0 42.9 7.0 16192 42479 0.0 50.0 8.016206 39621 0.0 42.9 7.0 16207 46007 0.0 50.0 8.0 16208 46015 0.0 62.58.0 16215 45301 0.0 37.5 8.0 16218 45303 0.0 37.5 8.0 16240 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1918344822 0.0 37.5 8.0 19201 44818 0.0 50.0 8.0 19235 45860 0.0 50.0 8.019247 45858 0.0 37.5 8.0 19258 42356 0.0 37.5 8.0 19259 42364 0.0 37.58.0 19268 45862 0.0 37.5 8.0 19286 43064 0.0 37.5 8.0 19326 45170 0.037.5 8.0 19329 43768 0.0 50.0 8.0 19346 43776 0.0 50.0 8.0 19349 451760.0 50.0 8.0 19378 42698 0.0 50.0 8.0 19383 45184 0.0 37.5 8.0 1939545878 0.0 37.5 8.0 19402 45884 0.0 37.5 8.0 19428 46020 0.0 37.5 8.019429 46032 0.0 50.0 8.0 19432 46026 0.0 37.5 8.0 19433 42516 0.0 50.08.0 19447 44117 0.0 50.0 8.0 19453 42719 0.0 50.0 8.0 19504 43423 0.050.0 8.0 19565 46233 0.0 37.5 8.0 19585 43054 0.0 50.0 8.0 19586 423520.0 37.5 8.0 19595 43746 0.0 50.0 8.0 19603 42366 0.0 50.0 8.0 1964040101 0.0 42.9 7.0 19646 39407 0.0 42.9 7.0 19688 38695 0.0 42.9 7.019692 40107 0.0 42.9 7.0 19701 39401 0.0 42.9 7.0 19706 39405 0.0 42.97.0 19713 38697 0.0 42.9 7.0 19826 42213 0.0 42.9 7.0 19860 38717 0.042.9 7.0 19871 38719 0.0 42.9 7.0 19909 38707 0.0 42.9 7.0 19924 387130.0 42.9 7.0 19945 39419 0.0 42.9 7.0 20018 42274 0.0 42.9 7.0 2002938772 0.0 42.9 7.0 20031 42286 0.0 42.9 7.0 20035 38770 0.0 42.9 7.020045 42282 0.0 42.9 7.0 20049 42284 0.0 42.9 7.0 20087 38774 0.0 42.97.0 20114 40313 0.0 42.9 7.0 20121 45625 0.0 50.0 8.0 20127 41005 0.042.9 7.0 20130 38203 0.0 42.9 7.0 20135 46325 0.0 37.5 8.0 20136 396110.0 42.9 7.0 20137 40309 0.0 57.1 7.0 20143 45619 0.0 37.5 8.0 2015341697 0.0 42.9 7.0 20156 38899 0.0 42.9 7.0 20160 38903 0.0 42.9 7.020161 41003 0.0 42.9 7.0 20163 40995 0.0 42.9 7.0 20165 46321 0.0 37.58.0 20167 41017 0.0 42.9 7.0 20172 42474 0.0 50.0 8.0 20185 42478 0.037.5 8.0 20187 41015 0.0 42.9 7.0 20202 41713 0.0 42.9 7.0 20204 424800.0 37.5 8.0 20207 43886 0.0 37.5 8.0 20218 43888 0.0 37.5 8.0 2023044586 0.0 37.5 8.0 20242 43188 0.0 37.5 8.0 20244 45304 0.0 62.5 8.020253 45996 0.0 37.5 8.0 20265 46016 0.0 37.5 8.0 20267 43198 0.0 37.58.0 20269 44606 0.0 50.0 8.0 20272 42496 0.0 50.0 8.0 20275 43900 0.037.5 8.0 20276 44608 0.0 37.5 8.0 20278 43902 0.0 75.0 8.0 20280 460060.0 37.5 8.0 20283 43192 0.0 37.5 8.0 20286 42490 0.0 37.5 8.0 2028943896 0.0 37.5 8.0 20295 42492 0.0 37.5 8.0 20297 46008 0.0 50.0 8.020307 39941 0.0 42.9 7.0 20314 42053 0.0 42.9 7.0 20331 38541 0.0 42.97.0 20333 42055 0.0 42.9 7.0 20340 39241 0.0 42.9 7.0 20361 40647 0.042.9 7.0 20374 41355 0.0 42.9 7.0 20376 39261 0.0 42.9 7.0 20385 399670.0 42.9 7.0 20387 38559 0.0 42.9 7.0 20390 40663 0.0 42.9 7.0 2039340669 0.0 42.9 7.0 20398 39263 0.0 42.9 7.0 20411 44930 0.0 37.5 8.020414 42071 0.0 42.9 7.0 20415 45638 0.0 37.5 8.0 20418 44228 0.0 37.58.0 20419 41371 0.0 42.9 7.0 20424 45640 0.0 50.0 8.0 20425 44163 0.037.5 8.0 20426 44171 0.0 37.5 8.0 20429 42818 0.0 50.0 8.0 20430 456340.0 50.0 8.0 20431 45644 0.0 50.0 8.0 20437 43471 0.0 37.5 8.0 2043843536 0.0 62.5 8.0 20443 44944 0.0 37.5 8.0 20444 45646 0.0 37.5 8.020447 44238 0.0 37.5 8.0 20448 44936 0.0 50.0 8.0 20451 44161 0.0 37.58.0 20459 44938 0.0 50.0 8.0 20460 45636 0.0 50.0 8.0 20467 44804 0.037.5 8.0 20473 44100 0.0 50.0 8.0 20534 46230 0.0 37.5 8.0 20537 455320.0 37.5 8.0 20547 45526 0.0 50.0 8.0 20563 45536 0.0 37.5 8.0 2058341535 0.0 42.9 7.0 20584 40123 0.0 57.1 7.0 20590 41525 0.0 42.9 7.020601 40817 0.0 42.9 7.0 20610 40821 0.0 42.9 7.0 20619 41529 0.0 42.97.0 20622 40825 0.0 42.9 7.0 20635 41527 0.0 42.9 7.0 20686 41527 0.042.9 7.0 20708 40823 0.0 42.9 7.0 20717 38758 0.0 57.1 7.0 20719 422290.0 42.9 7.0 20733 38764 0.0 42.9 7.0 20744 42235 0.0 42.9 7.0 2075842239 0.0 42.9 7.0 20825 39472 0.0 42.9 7.0 20912 40868 0.0 57.1 7.020928 40866 0.0 42.9 7.0 20940 41576 0.0 42.9 7.0 20968 40870 0.0 42.97.0 21055 39488 0.0 42.9 7.0 21107 40888 0.0 42.9 7.0 21130 40886 0.042.9 7.0 21140 40890 0.0 42.9 7.0 21155 41588 0.0 42.9 7.0 21176 415960.0 42.9 7.0 21218 42290 0.0 42.9 7.0 21242 43118 0.0 50.0 8.0 2129043114 0.0 62.5 8.0 21331 45220 0.0 37.5 8.0 21350 44518 0.0 37.5 8.021529 43120 0.0 37.5 8.0 21549 43812 0.0 50.0 8.0 21586 43810 0.0 50.08.0 21633 45224 0.0 50.0 8.0 21639 45226 0.0 37.5 8.0 21655 45922 0.037.5 8.0 21661 43265 0.0 37.5 8.0 21691 42573 0.0 37.5 8.0 21714 452320.0 37.5 8.0 21742 41161 0.0 71.4 7.0 21753 41163 0.0 42.9 7.0 2180244591 0.0 50.0 8.0 21805 43189 0.0 37.5 8.0 21807 45293 0.0 37.5 8.021808 42487 0.0 37.5 8.0 21811 43191 0.0 37.5 8.0 21815 38917 0.0 42.97.0 21819 38913 0.0 42.9 7.0 21826 41875 0.0 42.9 7.0 21827 45987 0.037.5 8.0 21837 45289 0.0 37.5 8.0 21838 45989 0.0 50.0 8.0 21969 445370.0 50.0 8.0 16070 44681 12.5 37.5 8.0 16076 43981 12.5 50.0 8.0 1606844675 37.5 0.0 8.0 16094 42428 37.5 0.0 8.0 19238 45866 37.5 0.0 8.017843 39216 42.9 0.0 7.0 18039 41657 42.9 0.0 7.0 21138 40188 42.9 0.07.0 16006 44200 50.0 0.0 8.0 19609 43404 50.0 0.0 8.0 16590 42108 57.10.0 7.0 20674 40125 57.1 0.0 7.0 17581 44634 62.5 0.0 8.0 17508 4639971.4 0.0 7.0 17968 38827 71.4 0.0 7.0 16007 44202 75.0 0.0 8.0 1796541244 85.7 0.0 7.0 16108 43970 87.5 0.0 8.0 16104 43972 100.0 0.0 8.0

Table 137 below provides the data for differential expression analysison the arrays using samples from metastazed colon tissue. In thisexample, the samples used for hybridization sequences on the microarraywere derived from the matched metastasized (MT) colon tissue and normal(N) colon tissues of the patients. Table 137 includes: 1) the SEQ ID NO:2) the percentage of patients tested in which expression levels of thegene (as detected using the correponding clone) was at least 2-foldgreater in metastisized cancerous colon tissue (MT) than in matchednormal tissue (“Colon>2×MT/N”); 5) the percentage of patients tested inwhich expression levels of the gene was less than or equal to one-halfof the expression level in matched normal cells (“Colon <=halfx T/N”);and 8) the colon number ratios, indicating the number of patients uponwhich the provided ratios was based. The corresponding data with thesame sequence of the colon tumor tissue versus matched normal colontissue (T/N) are provided for convenience in comparison. TABLE 137Polynucleotides Corresponding to Differnetially Expressed Genes inMetastasized Colon Cancer Tissue Colon MT/N SEQ Colon Colon MT/N < NumRatios Colon T/N > Colon T/N < Colon T/N ID NO MT/N > 2x halfx by Clone2x halfx Num Ratios 16207 40.0 0.0 5.0 0.0 50.0 8.0 16314 0.0 40.0 5.00.0 37.5 8.0 17643 0.0 40.0 5.0 0.0 37.5 8.0 17962 40.0 0.0 5.0 0.0 42.97.0 18336 20.0 40.0 5.0 0.0 85.7 7.0 18342 20.0 80.0 5.0 0.0 71.4 7.018343 20.0 40.0 5.0 0.0 85.7 7.0 18637 0.0 40.0 5.0 0.0 62.5 8.0 213310.0 40.0 5.0 0.0 37.5 8.0

Table 138 below provides the data for differential expression analysison the arrays using samples from matched cancerous and normal prostatetissue (PT/N). Table 138 includes: 1) the SEQ ID NO; 2) the percentageof patients tested in which expression levels of the gene (as detectedusing the correponding clone) was at least 2-fold greater inmetastisized cancerous prostate tissue (PT) than in matched normaltissue (“Colon>2×PT/N”); 3) the percentage of patients tested in whichexpression levels of the gene was less than or equal to one-half of theexpression level in matched normal cells (“Colon <=halfx PT/N”); and 4)the prostate PT/N number ratios, indicating the number of patients uponwhich the provided ratios was based. The corresponding data with thesame sequences for the colon tumor versus normal (T/N) and metastasizedcolon tissue versus normal (MT/N) are provided for convenience incomparison. TABLE 138 Polynucleotides Corresponding to DiffernetiallyExpressed Genes in Prostate Cancer Tissue Prostate Colon ProstateProstate (PT/N) Colon Colon Colon T/N Colon Colon MT/N SEQ (PT/N) >(PT/N) < Num T/N > T/N < Num MT/N > MT/N < Num ID NO 2x halfx Ratios 2xhalfx Ratios 2x halfx Ratios 16129 11.1 33.3 9.0 0.0 50.0 8.0 16480 37.512.5 8.0 0.0 71.4 7.0 16619 33.3 11.1 9.0 16634 12.5 37.5 8.0 0.0 42.97.0 17664 33.3 0.0 9.0 18336 37.5 25.0 8.0 0.0 85.7 7.0 20.0 40.0 5.018342 37.5 12.5 8.0 0.0 71.4 7.0 20.0 80.0 5.0 18410 22.2 33.3 9.0 1928633.3 0.0 9.0 0.0 37.5 8.0

Example 86 Antisense Regulation of Gene Expression

The expression of the differentially expressed genes represented by thepolynucleotides in the cancerous cells can be further analyzed usingantisense knockout technology to confirm the role and function of thegene product in tumorigenesis, e.g., in promoting a metastaticphenotype.

Methods for analysis using antisense technology are well known in theart. For example, a number of different oligonucleotides complementaryto the mRNA generated by the differentially expressed genes identifiedherein can be designed as antisense oligonucleotides, and tested fortheir ability to suppress expression of the genes. Sets of antisenseoligomers specific to each candidate target are designed using thesequences of the polynucleotides corresponding to a differentiallyexpressed gene and the software program HYBsimulator Version 4(available for Windows 95/Windows NT or for Power Macintosh, RNAture,Inc. 1003 Health Sciences Road, West, Irvine, Calif. 92612 USA). Factorsconsidered when designing antisense oligonucleotides include: 1) thesecondary structure of oligonucleotides; 2) the secondary structure ofthe target gene; 3) the specificity with no or minimumcross-hybridization to other expressed genes; 4) stability; 5) lengthand 6) terminal GC content. The antisense oligonucleotide is designed toso that it will hybridize to its target sequence under conditions ofhigh stringency at physiological temperatures (e.g., an optimaltemperature for the cells in culture to provide for hybridization in thecell, e.g., about 37° C.), but with minimal formation of homodimers.

Once synthesized and quantitated, the oligomers are screened forefficiency of a transcript knock-out in a panel of cancer cell lines.The efficiency of the knock-out is determined by analyzing mRNA levelsusing lightcycler quantification. The oligomers that resulted in thehighest level of transcript knock-out, wherein the level was at leastabout 50%, preferably about 80-90%, up to 95% or more up to undetectablemessage, are selected for use in a cell-based proliferation assay, ananchorage independent growth assay, and an apoptosis assay.

For example, where the polynucleotide is identified as having a role incolon cancer, the ability of the corresponding designed antisenseoligonucleotide to inhibit gene expression is tested throughtransfection into SW620 colon colorectal carcinoma cells. For eachtransfection mixture, a carrier molecule, preferably a lipitoid orcholesteroid, is prepared to a working concentration of 0.5 mM in water,sonicated to yield a uniform solution, and filtered through a 0.45 μmPVDF membrane. The antisense or control oligonucleotide is then preparedto a working concentration of 100 μM in sterile Millipore water. Theoligonucleotide is further diluted in OptiMEM™ (Gibco/BRL), in amicrofuge tube, to 2 μM, or approximately 20 μg oligo/ml of OptiMEM™. Ina separate microfuge tube, lipitoid or cholesteroid, typically in theamount of about 1.5-2 nmol lipitoid/μg antisense oligonucleotide, isdiluted into the same volume of OptiMEM™ used to dilute theoligonucleotide. The diluted antisense oligonucleotide is immediatelyadded to the diluted lipitoid and mixed by pipetting up and down.Oligonucleotide is added to the cells to a final concentration of 30 nM.

The level of target mRNA that corresponds to a target gene of interestin the transfected cells is quantitated in the cancer cell lines usingthe Roche LightCycler™ real-time PCR machine. Values for the target mRNAare normalized versus an internal control (e.g., beta-actin). For each20 μl reaction, extracted RNA (generally 0.2-1 μg total) is placed intoa sterile 0.5 or 1.5 ml microcentrifuge tube, and water added to a totalvolume of 12.5 μl. To each tube 7.5 μl of a buffer/enzyme mixture isadded, which is prepared by mixing (in the order listed) 2.5 μl H₂O, 2.0μl 10× reaction buffer, 10 μl oligo dT (20 pmol), 1.0 μl dNTP mix (10 mMeach), 0.5 μl RNAsin® (20 u) (Ambion, Inc., Hialeah, Fla.), and 0.5 μlMMLV reverse transcriptase (50 u) (Ambion, Inc.). The contents are mixedby pipetting up and down, and the reaction mixture incubated at 42° C.for 1 hour. The contents of each tube are centrifuged prior toamplification.

An amplification mixture is prepared by mixing in the following order:1×PCR buffer II, 3 mM MgCl₂, 140 μM each dNTP, 0.175 pmol each oligo,1:50,000 dil of SYBR® Green, 0.25 mg/ml BSA, 1 unit Taq polymerase, andH₂₀ to 20 μl. (PCR buffer II is available in 10× concentration fromPerkin-Elmer, Norwalk, Conn.). In 1× concentration it contains 10 mMTris pH 8.3 and 50 mM KCl. SYBR® Green (Molecular Probes, Eugene, Oreg.)is a dye which fluoresces when bound to double stranded DNA. As doublestranded PCR product is produced during amplification, the fluorescencefrom SYBR® Green increases. To each 20 μl aliquot of amplificationmixture, 2 μl of template RT are added, and amplification carried outaccording to standard protocols.

The results can be expressed as the percent decrease in expression ofthe corresponding gene product relative to non-transfected cells,vehicle-only transfected (mock-transfected) cells, or cells transfectedwith reverse control oligonucleotides.

Example 87 Effect of Expression on Proliferation

The effect of gene expression on the inhibition of cell proliferationcan be assessed in, for example, metastatic breast cancer cell lines(MDA-MB-231 (“231”)), SW620 colon colorectal carcinoma cells, or SKOV3cells (a human ovarian carcinoma cell line).

Cells are plated to approximately 60-80% confluency in 96-well dishes.Antisense or reverse control oligonucleotide iss diluted to 2 μM inOptiMEM™ and added to OptiMEM™ into which the delivery vehicle, lipitoid116-6 in the case of SW620 cells or 1:1 lipitoid 1:cholesteroid 1 in thecase of MDA-MB-231 cells, had been diluted. The oligo/delivery vehiclemixture is then further diluted into medium with serum on the cells. Thefinal concentration of oligonucleotide for all experiments was 300 nM,and the final ratio of oligo to delivery vehicle for all experiments iss1.5 nmol lipitoid/μg oligonucleotide.

Antisense oligonucleotides are prepared as described above (see Example86). Cells are transfected overnight at 37° C. and the transfectionmixture replaced with fresh medium the next morning. Transfection iscarried out as described above in Example 83.

Those antisense oligonucleotides that inhibit proliferation representgenes that play a role in production or maintenance of the cancerousphenotype.

Example 88 Effect of Gene Expression on Colony Formation

The effect of gene expression upon colony formation of, for example,SW620 cells, SKOV3 cells, and MD-MBA-231 cells can be tested in a softagar assay. Soft agar assays are conducted by first establishing abottom layer of 2 ml of 0.6% agar in media plated fresh within a fewhours of layering on the cells. The cell layer is formed on the bottomlayer by removing cells transfected as described above from plates using0.05% trypsin and washing twice in media. The cells are counted in aCoulter counter, and resuspended to 106 per ml in media. 10 μl aliquotsare placed with media in 96-well plates (to check counting with WST1),or diluted further for the soft agar assay. 2000 cells are plated in 800μl 0.4% agar in duplicate wells above 0.6% agar bottom layer. After thecell layer agar solidifies, 2 ml of media is dribbled on top andantisense or reverse control oligo (produced as described in Example 86)added without delivery vehicles. Fresh media and oligos are added every3-4 days. Colonies usually are expected to form in 10 days to 3 weeks.Fields of colonies are counted by eye. Wst-1 metabolism values can beused to compensate for small differences in starting cell number. Largerfields can be scanned for visual record of differences.

Those antisense oligonucleotides that inhibited colony formationrepresent genes that play a role in production or maintenance of thecancerous phenotype.

Example 89 Induction of Cell Death upon Depletion of Polypeptides byDepletion of mRNA (“Antisense Knockout”)

In order to assess the effect of depletion of a target message upon celldeath, SW620 cells, or other cells derived from a cancer of interest,are transfected for proliferation assays. For cytotoxic effect in thepresence of cisplatin (cis), the same protocol is followed but cells areleft in the presence of 2 μM drug. Each day, cytotoxicity was monitoredby measuring the amount of LDH enzyme released in the medium due tomembrane damage. The activity of LDH is measured using the CytotoxicityDetection Kit from Roche Molecular Biochemicals. The data is provided asa ratio of LDH released in the medium vs. the total LDH present in thewell at the same time point and treatment (rLDH/tLDH). A positivecontrol using antisense and reverse control oligonucleotides for BCL2 (aknown anti-apoptotic gene) is included; loss of message for BCL2 leadsto an increase in cell death compared with treatment with the controloligonucleotide (background cytotoxicity due to transfection).

Example 90 Functional Analysis of Gene Products Differentially Expressedin Cancer

The gene products of sequences of a gene differentially expressed incancerous cells can be further analyzed to confirm the role and functionof the gene product in tumorigenesis, e.g., in promoting or inhibitingdevelopment of a metastatic phenotype. For example, the function of geneproducts corresponding to genes identified herein can be assessed byblocking function of the gene products in the cell. For example, wherethe gene product is secreted or associated with a cell surface membrane,blocking antibodies can be generated and added to cells to examine theeffect upon the cell phenotype in the context of, for example, thetransformation of the cell to a cancerous, particularly a metastatic,phenotype.

Where the gene product of the differentially expressed genes identifiedherein exhibits sequence homology to a protein of known function (e.g.,to a specific kinase or protease) and/or to a protein family of knownfunction (e.g., contains a domain or other consensus sequence present ina protease family or in a kinase family), then the role of the geneproduct in tumorigenesis, as well as the activity of the gene product,can be examined using small molecules that inhibit or enhance functionof the corresponding protein or protein family.

Additional functional assays include, but are not necessarily limitedto, those that analyze the effect of expression of the correspondinggene upon cell cycle and cell migration. Methods for performing suchassays are well known in the art.

Example 91 Contig Assembly and Additional Gene Characterization

The sequences of the polynucleotides provided in the present inventioncan be used to extend the sequence information of the gene to which thepolynucleotides correspond (e.g., a gene, or mRNA encoded by the gene,having a sequence of the polynucleotide described herein). This expandedsequence information can in turn be used to further characterize thecorresponding gene, which in turn provides additional information aboutthe nature of the gene product (e.g., the normal function of the geneproduct). The additional information can serve to provide additionalevidence of the gene product's use as a therapeutic target, and providefurther guidance as to the types of agents that can modulate itsactivity.

For example, a contig can be assembled using the sequence of apolynucleotide described herein. A “contig” is a contiguous sequence ofnucleotides that is assembled from nucleic acid sequences havingoverlapping (e.g., shared or substantially similar) sequenceinformation. The sequences of publicly-available ESTs (ExpressedSequence Tags) and the sequences of various clones from several cDNAlibraries synthesized at Chiron were used in the contig assembly. Thecontig is assembled using the software program Sequencher, version 4.05,according to the manufacturer's instructions. The resulting contig canthen be used to search both the public databases as well as databasesinternal to the applicatns to match the polynucleotide contiged withhomology data and/or differential gene expressed data.

The sequence information obtained in the contig assembly described abovecan be used to obtain a consensus sequence derived from the contig usingthe Sequencher program. The consensus sequence can then be used as aquery sequence in a BLASTN search of the DGTI DoubleTwist Gene Index(DoubleTwist, Inc., Oakland, Calif.), which contains all the EST andnon-redundant sequence in public databases. Alternatively, a sequence ofa polynucleotide described herein can be used directly as a querysequence in a BLASTN search of the DGTI DoubleTwist Gene Index.

Through contig assembly and the use of homology searching softwareprograms, the sequence information provided herein can be readilyextended to confirm, or confirm a predicted, gene having the sequence ofthe polynucleotides described in the present invention. Further theinformation obtained can be used to identify the function of the geneproduct of the gene corresponding to the polynucleotides describedherein. While not necessary to the practice of the invention,identification of the function of the corresponding gene, can provideguidance in the design of therapeutics that target the gene to modulateits activity and modulate the cancerous phenotype (e.g., inhibitmetastasis, proliferation, and the like).

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims. Those skilled in the art will recognize,or be able to ascertain, using not more than routine experimentation,many equivalents to the specific embodiments of the invention describedherein. Such specific embodiments and equivalents are intended to beencompassed by the following claims.

Deposit Information.

A deposit of the biological materials in the tables referenced below wasmade with the American Type Culture Collection, 10801 University Blvd.,Manasas, Va. 20110-2209, under the provisions of the Budapest Treaty, onor before the filing date of the present application. The accessionnumber indicated is assigned after successful viability testing, and therequisite fees were paid. Access to said cultures will be availableduring pendency of the patent application to one determined by theCommissioner to be entitled to such under 37 C.F.R. §1.14 and 35 U.S.C.§122. All restriction on availability of said cultures to the publicwill be irrevocably removed upon the granting of a patent based upon theapplication. Moreover, the designated deposits will be maintained for aperiod of thirty (30) years from the date of deposit, or for five (5)years after the last request for the deposit; or for the enforceablelife of the U.S. patent, whichever is longer. Should a culture becomenonviable or be inadvertently destroyed, or, in the case ofplasmid-containing strains, lose its plasmid, it will be replaced with aviable culture(s) of the same taxonomic description.

These deposits are provided merely as a convenience to those of skill inthe art, and are not an admission that a deposit is required. A licensemay be required to make, use, or sell the deposited materials, and nosuch license is hereby granted. The deposit below was received by theATCC on or before the filing date of the present application. TABLE 139Cell Lines Deposited with ATCC ATCC CMCC Cell Line Deposit DateAccession No. Accession No. KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12CMay 15, 1998 CRL-12533 11611 MDA-MB- May 15, 1998 CRL-12532 10583 231MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containingspecific clones, were assigned an “ES” number (internal reference) anddeposited with the ATCC. Table 141 below provides the ATCC AccessionNos. of the ES deposits, all of which were deposited on or before Jun.13, 2000. TABLE 140 Pools of Clones and Libraries Deposited with ATCC onor before Jun. 13, 2000. Library No. CMCC No. ATCC Accession No. ES 1685276 PTA-2027 ES 169 5277 PTA-2028 ES 170 5284 PTA-2029 ES 171 5285PTA-2030 ES 172 5286 PTA-2031 ES 173 5287 PTA-2032 ES 174 5288 PTA-2033ES 175 5289 PTA-2034 ES 176 5290 PTA-2035 ES 177 5291 PTA-2036 ES 1785292 PTA-2037 ES 179 5293 PTA-2038 ES 180 5294 PTA-2039 ES 181 5295PTA-2040 ES 182 5296 PTA-2041 ES 183 5297 PTA-2042 ES 184 5298 PTA-2043ES 185 5299 PTA-2044 ES 186 5301 PTA-2045 ES 187 5302 PTA-2046 ES 1885303 PTA-2047 ES 189 5304 PTA-2052 ES 190 5305 PTA-2053 ES 191 5306PTA-2054 ES 192 5307 PTA-2055 ES 193 5308 PTA-2056 ES 194 5309 PTA-2057ES 195 5310 PTA-2058 ES 196 5311 PTA-2059 ES 197 5312 PTA-2060 ES 1985313 PTA-2061 ES 199 5314 PTA-2062 ES 200 5315 PTA-2048 ES 201 5316PTA-2049 ES 202 5317 PTA-2063 ES 203 5318 PTA-2064 ES 204 5319 PTA-2065ES 205 5320 PTA-2066 ES 206 5321 PTA-2067 ES 207 5322 PTA-2068 ES 2085253 PTA-2050 ES 209 5324 PTA-2051

Table 141 (inserted before the claims) provides the clones in each ofthe above libraries.

Retrieval of Individual Clones from Deposit of Pooled Clones. Where theATCC deposit is composed of a pool of cDNA clones or a library of cDNAclones, the deposit was prepared by first transfecting each of theclones into separate bacterial cells. The clones in the pool or librarywere then deposited as a pool of equal mixtures in the compositedeposit. Particular clones can be obtained from the composite depositusing methods well known in the art. For example, a bacterial cellcontaining a particular clone can be identified by isolating singlecolonies, and identifying colonies containing the specific clone throughstandard colony hybridization techniques, using an oligonucleotide probeor probes designed to specifically hybridize to a sequence of the cloneinsert (e.g., a probe based upon unmasked sequence of the encodedpolynucleotide having the indicated SEQ ID NO). The probe should bedesigned to have a T_(m) of approximately 80° C. (assuming 2° C. foreach A or T and 4° C. for each G or C). Positive colonies can then bepicked, grown in culture, and the recombinant clone isolated.Alternatively, probes designed in this manner can be used to PCR toisolate a nucleic acid molecule from the pooled clones according tomethods well known in the art, e.g., by purifying the cDNA from thedeposited culture pool, and using the probes in PCR reactions to producean amplified product having the corresponding desired polynucleotidesequence.

Example 92 Source of Biological Materials and Overview of NovelPolynucleotides Expressed by the Biological Materials

Candidate polynucleotides that may represent novel polynucleotides wereobtained from cDNA libraries generated from selected cell lines andpatient tissues. In order to obtain the candidate polynucleotides, mRNAwas isolated from several selected cell lines and patient tissues, andused to construct cDNA libraries. The cells and tissues that served assources for these cDNA libraries are summarized in Table 142 below.

Human colon cancer cell line Km12L4-A (Morikawa, et al., Cancer Research(1988) 48:6863) is derived from the KM12C cell line. The KM12C cell line(Morikawa et al. Cancer Res. (1988) 48:1943-1948), which is poorlymetastatic (low metastatic) was established in culture from a Dukes'stage B2 surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863).The KM12L4-A is a highly metastatic subline derived from KM12C (Yeatmanet al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu.Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C andKM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) arewell-recognized in the art as a model cell line for the study of coloncancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. CancerRes. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin.Exp. Metastasis (1996) 14:246).

The MDA-MB-231 cell line (Brinkley et al. Cancer Res. (1980)40:3118-3129) was originally isolated from pleural effusions (Cailleau,J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential,and forms poorly differentiated adenocarcinoma grade II in nude miceconsistent with breast carcinoma. The MCF7 cell line was derived from apleural effusion of a breast adenocarcinoma and is non-metastatic. TheMV-522 cell line is derived from a human lung carcinoma and is of highmetastatic potential. The UCP-3 cell line is a low metastatic human lungcarcinoma cell line; the MV-522 is a high metastatic variant of UCP-3.These cell lines are well-recognized in the art as models for the studyof human breast and lung cancer (see, e.g., Chandrasekaran et al.,Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J MedChem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer(1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res(1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987)40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 andUCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner etal., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., AnticancerDrugs (1997) 8:696 (MV522)).

The samples of libraries 15-20 are derived from two different patients(UC#2, and UC#3). The bFGF-treated HMVEC were prepared by incubationwith bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMVEC were prepared byincubation with 20 ng/ml VEGF for 2 hrs. Following incubation with therespective growth factor, the cells were washed and lysis buffer addedfor RNA preparation.

GRRpz was derived from normal prostate epithelium. The WOca cell line isa Gleason Grade 4 cell line.

The source materials for generating the normalized prostate libraries oflibraries 25 and 26 were cryopreserved prostate tumor tissue from apatient with Gleason grade 3+3 adenocarcinoma and matched normalprostate biopsies from a pool of at-risk subjects under medicalsurveillance. The source materials for generating the normalizedprostate libraries of libraries 30 and 31 were cryopreserved prostatetumor tissue from a patient with Gleason grade 4+4 adenocarcinoma andmatched normal prostate biopsies from a pool of at-risk subjects undermedical surveillance.

The source materials for generating the normalized breast libraries oflibraries 27, 28 and 29 were cryopreserved breast tissue from a primarybreast tumor (infiltrating ductal carcinoma)(library 28), from a lymphnode metastasis (library 29), or matched normal breast biopsies from apool of at-risk subjects under medical surveillance. In each case,prostate or breast epithelia were harvested directly from frozensections of tissue by laser capture microdissection (LCM, ArcturusEnginering Inc., Mountain View, Calif.), carried out according tomethods well known in the art (see, Simone et al. Am J Pathol.156(2):445-52 (2000)), to provide substantially homogenous cell samples.TABLE 142 Description of cDNA Libraries Number Library of Clones (lib#)Description in Library 0 Artificial library composed of deselectedclones (clones with no 673 associated variant or cluster) 1 Human ColonCell Line Km12 L4: High Metastatic Potential 308731 (derived from Km12C)2 Human Colon Cell Line Km12C: Low Metastatic Potential 284771 3 HumanBreast Cancer Cell Line MDA-MB-231: High Metastatic 326937 Potential;micro-mets in lung 4 Human Breast Cancer Cell Line MCF7: Non Metastatic318979 8 Human Lung Cancer Cell Line MV-522: High Metastatic Potential223620 9 Human Lung Cancer Cell Line UCP-3: Low Metastatic Potential312503 12 Human microvascular endothelial cells (HMEC) - UNTREATED 41938(PCR (OligodT) cDNA library) 13 Human microvascular endothelial cells(HMEC) - bFGF TREATED 42100 (PCR (OligodT) cDNA library) 14 Humanmicrovascular endothelial cells (HMEC) - VEGF TREATED 42825 (PCR(OligodT) cDNA library) 15 Normal Colon - UC#2 Patient (MICRODISSECTEDPCR (OligodT) 282722 cDNA library) 16 Colon Tumor - UC#2 Patient(MICRODISSECTED PCR (OligodT) 298831 cDNA library) 17 Liver Metastasisfrom Colon Tumor of UC#2 Patient 303467 (MICRODISSECTED PCR (OligodT)cDNA library) 18 Normal Colon - UC#3 Patient (MICRODISSECTED PCR(OligodT) 36216 cDNA library) 19 Colon Tumor - UC#3 Patient(MICRODISSECTED PCR (OligodT) 41388 cDNA library) 20 Liver Metastasisfrom Colon Tumor of UC#3 Patient 30956 (MICRODISSECTED PCR (OligodT)cDNA library) 21 GRRpz Cells derived from normal prostate epithelium164801 22 WOca Cells derived from Gleason Grade 4 prostate cancer 162088epithelium 23 Normal Lung Epithelium of Patient #1006 (MICRODISSECTED306198 PCR (OligodT) cDNA library) 24 Primary tumor, Large CellCarcinoma of Patient #1006 309349 (MICRODISSECTED PCR (OligodT) cDNAlibrary) 25 Normal Prostate Epithelium from Patient IF97-26811 279444 26Prostate Cancer Epithelium Gleason 3 + 3 Patient IF97-26811 269406 27Normal Breast Epithelium from Patient 515 239494 28 Primary Breast tumorfrom Patient 515 259960 29 Lymph node metastasis from Patient 515 32678630 Normal Prostate Epithelium from Chiron Patient ID 884 298431 31Prostate Cancer Epithelium (Gleason 4 + 4) from Chiron Patient ID 331941884

Characterization of Sequences in the Libraries

After using the software program Phred (ver 0.000925.c, Green and Weing,©1993-2000) to select those polynucleotides having the best qualitysequence, the polynucleotides were compared against the public databasesto identify any homologous sequences. The sequences of the isolatedpolynucleotides were first masked to eliminate low complexity sequencesusing the RepeatMasker masking program, publicly available through a website supported by the University of Washington (See also Smit, A. F. A.and Green, P., unpublished results). Generally, masking does notinfluence the final search results, except to eliminate sequences ofrelatively little interest due to their low complexity, and to eliminatemultiple “hits” based on similarity to repetitive regions common tomultiple sequences, e.g., Alu repeats.

The remaining sequences were then used in a homology search of theGenBank database using the TeraBLAST program (TimeLogic, Crystal Bay,Nev.). TeraBLAST is a version of the publicly available BLAST searchalgorithm developed by the National Center for Biotechnology, modifiedto operate at an accelerated speed with increased sensitivity on aspecialized computer hardware platform. The program was run with thedefault parameters recommended by TimeLogic to provide the bestsensitivity and speed for searching DNA and protein sequences. Sequencesthat exhibited greater than 70% overlap, 99% identity, and a p value ofless than 1×10e−40 were discarded. Sequences from this search also werediscarded if the inclusive parameters were met, but the sequence wasribosomal or vector-derived.

The resulting sequences from the previous search were classified intothree groups (1, 2 and 3 below) and searched in a TeraBLASTX vs. NRP(non-redundant proteins) database search: (1) unknown (no hits in theGenBank search), (2) weak similarity (greater than 45% identity and pvalue of less than 1×10e−5), and (3) high similarity (greater than 60%overlap, greater than 80% identity, and p value less than 1×10e−5).Sequences having greater than 70% overlap, greater than 99% identity,and p value of less than 1×10e−40 were discarded.

The remaining sequences were classified as unknown (no hits), weaksimilarity, and high similarity (parameters as above). Two searches wereperformed on these sequences. First, a TeraBLAST vs. EST database searchwas performed and sequences with greater than 99% overlap, greater than99% similarity and a p value of less than 1×10e−40 were discarded.Sequences with a p value of less than 1×10e−65 when compared to adatabase sequence of human origin were also excluded. Second, aTeraBLASTN vs. Patent GeneSeq database was performed and sequenceshaving greater than 99% identity, p value less than 1×10e−40, andgreater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rulesand redundancies in the dataset. Sequences with a p value of less than1×10e−111 in relation to a database sequence of human origin werespecifically excluded. The final result provided the sequences listed asSEQ ID NOS:22001-23267 in the accompanying Sequence Listing andsummarized in Table 143 (inserted prior to claims). Each identifiedpolynucleotide represents sequence from at least a partial mRNAtranscript.

Summary of Polynucleotides of the Invention

Table 143 (inserted prior to claims) provides a summary ofpolynucleotides isolated as described. Specifically, Table 143provides: 1) the SEQ ID NO (“SEQ ID”) assigned to each sequence for usein the present specification; 2) the Cluster Identification No.(“CLUSTER”); 3) the Sequence Name assigned to each sequence; 3) thesequence name (“SEQ NAME”) used as an internal identifier of thesequence; 4) the orientation of the sequence (“ORIENT”) (either forward(F) or reverse (R)); 5) the name assigned to the clone from which thesequence was isolated (“CLONE ID”); and 6) the name of the library fromwhich the sequence was isolated (“LIBRARY”). Because at least some ofthe provided polynucleotides represent partial mRNA transcripts, two ormore polynucleotides may represent different regions of the same mRNAtranscript and the same gene and/or may be contained within the sameclone. Thus, for example, if two or more SEQ ID NOS: are identified asbelonging to the same clone, then either sequence can be used to obtainthe full-length mRNA or gene. Clones which comprise the sequencesdescribed herein were deposited as set out in the tables indicated below(see Example entitled “Deposit Information”).

Example 93 Contig Assembly

The sequences of the polynucleotides provided in the present inventioncan be used to extend the sequence information of the gene to which thepolynucleotides correspond (e.g., a gene, or mRNA encoded by the gene,having a sequence of the polynucleotide described herein). This expandedsequence information can in turn be used to further characterize thecorresponding gene, which in turn provides additional information aboutthe nature of the gene product (e.g., the normal function of the geneproduct). The additional information can serve to provide additionalevidence of the gene product's use as a therapeutic target, and providefurther guidance as to the types of agents that can modulate itsactivity.

For example, a contig was assembled using the sequence of apolynucleotide described herein. A “contig” is a contiguous sequence ofnucleotides that is assembled from nucleic acid sequences havingoverlapping (e.g., shared or substantially similar) sequenceinformation. The sequences of publicly-available ESTs (ExpressedSequence Tags) and the sequences of various of the above-describedpolynucleotides were used in the contig assembly. The contig wasassembled using the software program Sequencher, version 4.05, accordingto the manufacturer's instructions. The sequence information obtained inthe contig assembly was then used to obtain a consensus sequence derivedfrom the contig using the Sequencher program. The resulting consensussequence was used to search both the public databases as well asdatabases internal to the applicants to match the consensuspolynucleotide with homology data and/or differential gene expresseddata.

The final result provided the sequences listed as SEQ ID NOS:23268-23385 in the accompanying Sequence Listing and summarized in Table144 (inserted prior to claims). Table 144 provides a summary of theconsensus sequences assembled as described. Specifically, Table 144provides: 1) the SEQ ID NO (“SEQ ID”) assigned to each sequence for usein the present specification; 2) the consensus sequence name (“CONSENSUSSEQ NAME”) used as an internal identifier of the sequence; and 3) thesequence name (“POLYNTD SEQ NAME”) of a polynucleotide of SEQ ID NOS:22001-23267 used in assembly of the consensus sequence. TABLE 144CONSENSUS SEQ ID SEQ NAME POLYNTD SEQ NAME 23268 Clu1009284.12490.J22.GZ43_363450 23269 Clu1022935.2 2561.O19.GZ43_376586 23270Clu1037152.1 2558.L19.GZ43_374594 23271 Clu13903.1 2489.A13.GZ43_36284123272 Clu139979.2 2504.B21.GZ43_365834 23273 Clu163602.22561.H17.GZ43_376416 23274 Clu187860.2 2474.P22.GZ43_361999 23275Clu189993.1 2505.N19.GZ43_366504 23276 Clu20975.1 2466.F16.GZ43_36021723277 Clu217122.1 2458.N10.GZ43_356930 23278 Clu218833.12562.O01.GZ43_375800 23279 Clu244504.2 2367.E23.GZ43_346113 23280Clu271456.1 2365.G19.GZ43_345389 23281 Clu376516.1 2457.J23.GZ43_35645123282 Clu376630.1 2467.B11.GZ43_360500 23283 Clu377044.22499.A22.GZ43_365257 23284 Clu379689.1 2540.M18.GZ43_372313 23285Clu380482.2 2542.D09.GZ43_372856 23286 Clu387530.4 2475.N08.GZ43_36232123287 Clu388450.2 2497.L05.GZ43_364736 23288 Clu396325.12561.P16.GZ43_376607 23289 Clu397115.3 2560.K18.GZ43_375337 23290Clu398642.2 2542.N22.GZ43_373109 23291 Clu400258.1 2504.O12.GZ43_36613723292 Clu402167.1 2540.C21.GZ43_372076 23293 Clu402591.32483.E11.GZ43_359762 23294 Clu402904.1 2504.J02.GZ43_366007 23295Clu404081.2 2483.K02.GZ43_359897 23296 Clu411524.1 2497.C11.GZ43_36452623297 Clu41346.1 2560.K08.GZ43_375327 23298 Clu415520.12561.L14.GZ43_376509 23299 Clu416124.1 2367.G17.GZ43_346155 23300Clu417672.1 2367.I09.GZ43_346195 23301 Clu423664.1 2488.H12.GZ43_36262423302 Clu429609.1 2457.M11.GZ43_356511 23303 Clu442923.32498.G15.GZ43_365010 23304 Clu446975.1 2459.K15.GZ43_357247 23305Clu449839.2 2497.O09.GZ43_364812 23306 Clu449889.1 2475.N21.GZ43_36233423307 Clu451707.2 2554.P16.GZ43_376223 23308 Clu454509.32542.M09.GZ43_373072 23309 Clu454796.1 2540.P02.GZ43_372369 23310Clu455862.1 2560.I09.GZ43_375280 23311 Clu460493.1 2483.O07.GZ43_35999823312 Clu464200.1 2465.G06.GZ43_358214 23313 Clu465446.22457.L21.GZ43_356497 23314 Clu470032.1 2474.C01.GZ43_361666 23315Clu474125.1 2457.E23.GZ43_356331 23316 Clu474125.2 2541.A06.GZ43_37239723317 Clu477271.1 2540.E17.GZ43_372120 23318 Clu480410.12498.H08.GZ43_365027 23319 Clu483211.2 2510.J18.GZ43_369259 23320Clu497138.1 2458.N19.GZ43_356939 23321 Clu498886.1 2465.L22.GZ43_35835023322 Clu498886.2 2541.B15.GZ43_372430 23323 Clu5013.22559.D05.GZ43_374772 23324 Clu5105.2 2542.D19.GZ43_372866 23325Clu510539.2 2558.H17.GZ43_374496 23326 Clu514044.1 2367.F13.GZ43_34612723327 Clu516526.1 2456.F23.GZ43_355971 23328 Clu519176.22559.H20.GZ43_374883 23329 Clu520370.1 2541.N01.GZ43_372704 23330Clu524917.1 2464.H05.GZ43_357853 23331 Clu528957.1 2540.F15.GZ43_37214223332 Clu533888.1 2557.L23.GZ43_374214 23333 Clu534076.12456.C05.GZ43_355881 23334 Clu540142.2 2456.H02.GZ43_355998 23335Clu540379.2 2491.O02.GZ43_363934 23336 Clu549507.1 2483.B23.GZ43_35970223337 Clu551338.3 2457.I12.GZ43_356416 23338 Clu552537.22540.C10.GZ43_372065 23339 Clu556827.3 2558.E24.GZ43_374431 23340Clu558569.2 2558.D03.GZ43_374386 23341 Clu565709.1 2542.P02.GZ43_37313723342 Clu568204.1 2456.M05.GZ43_356121 23343 Clu570804.12475.M20.GZ43_362309 23344 Clu572170.2 2557.H03.GZ43_374098 23345Clu573764.1 2365.C10.GZ43_345284 23346 Clu587168.1 2483.F15.GZ43_35979023347 Clu588996.1 2466.G06.GZ43_360231 23348 Clu597681.12459.A04.GZ43_356996 23349 Clu598388.1 2562.E03.GZ43_375562 23350Clu604822.2 2504.F20.GZ43_365929 23351 Clu621573.1 2535.A08.GZ43_37009523352 Clu625055.1 2511.A07.GZ43_369416 23353 Clu627263.12466.D20.GZ43_360173 23354 Clu635332.1 2480.D13.GZ43_358588 23355Clu640911.2 2541.M24.GZ43_372703 23356 Clu641662.2 2555.D22.GZ43_37325323357 Clu659483.1 2365.F12.GZ43_345358 23358 Clu6712.12535.P14.GZ43_370461 23359 Clu676448.3 2464.B01.GZ43_357705 23360Clu682065.2 2467.E19.GZ43_360580 23361 Clu685244.2 2561.J01.GZ43_37644823362 Clu691653.1 2560.O12.GZ43_375427 23363 Clu692282.12561.I11.GZ43_376434 23364 Clu697955.1 2557.J22.GZ43_374165 23365Clu702885.3 2555.H18.GZ43_373345 23366 Clu70908.1 2561.C15.GZ43_37629423367 Clu709796.2 2542.C20.GZ43_372843 23368 Clu715752.12459.A24.GZ43_357016 23369 Clu727966.1 2489.F09.GZ43_362957 23370Clu732950.2 2475.L17.GZ43_362282 23371 Clu752623.2 2561.I07.GZ43_37643023372 Clu756337.1 2561.I19.GZ43_376442 23373 Clu782981.12489.L05.GZ43_363097 23374 Clu805118.3 2480.D16.GZ43_358591 23375Clu806992.2 2467.D20.GZ43_360557 23376 Clu823296.3 2558.P20.GZ43_37469123377 Clu830453.2 2540.M22.GZ43_372317 23378 Clu839006.12507.H02.GZ43_367111 23379 Clu847088.1 2542.H23.GZ43_372966 23380Clu853371.2 2491.I06.GZ43_363794 23381 Clu88462.1 2510.K15.GZ43_36928023382 Clu935908.2 2505.O09.GZ43_366518 23383 Clu948383.12541.F05.GZ43_372516 23384 Clu966599.3 2507.L12.GZ43_367217 23385Clu993554.1 2558.F19.GZ43_374450

Example 94 Additional Gene Characterization

Sequences of the polynucleotides of SEQ ID NOS: 22001-23267 were used asa query sequence in a TeraBLASTN search of the DoubleTwist Human GenomeSequence Database (DoubleTwist, Inc., Oakland, Calif.), which containsall the human genomic sequences that have been assembled into acontiguous model of the human genome. Predicted cDNA and proteinsequences were obtained where a polynucleotide of the invention washomologous to a predicted full-length gene sequence. Alternatively, asequence of a contig or consensus sequence described herein could beused directly as a query sequence in a TeraBLASTN search of theDoubleTwist Human Genome Sequence Database.

The final results of the search provided the predicted cDNA sequenceslisted as SEQ ID NOS: 1386-1477 in the accompanying Sequence Listing andsummarized in Table 145 (inserted prior to claims), and the predictedprotein sequences listed as SEQ ID NOS:23478-23568 in the accompanyingSequence Listing and summarized in Table 146 (inserted prior to claims).Specifically, Table 145 provides: 1) the SEQ ID NO (“SEQ ID”) assignedto each cDNA sequence for use in the present specification; 2) the cDNAsequence name (“cDNA SEQ NAME”) used as an internal identifier of thesequence; 3) the sequence name (“POLYNTD SEQ NAME”) of thepolynucleotide of SEQ ID NO that maps to the cDNA; 4) The gene id number(GENE) of the DoubleTwist predicted gene; 5) the chromosome (“CHROM”)containing the gene corresponding to the cDNA sequence; Table 146provides: 1) the SEQ ID NO (“SEQ ID”) assigned to each protein sequencefor use in the present specification; 2) the protein sequence name(“PROTEIN SEQ NAME”) used as an internal identifier of the sequence; 3)the sequence name (“POLYNTD SEQ NAME”) of the polynucleotide of SEQ IDNOS: 22001-23267 that maps to the protein sequence; 4) The gene idnumber (GENE) of the DoubleTwist predicted gene; 5) the chromosome(“CHROM”) containing the gene corresponding to the cDNA sequence. TABLE145 cDNA SEQ POLYNTD SEQ SEQ ID NAME NAME GENE CHROM 23386 DTT00087024.12467.H18.GZ43_360651 DTG00087008.1 1 23387 DTT00089020.12367.I15.GZ43_346201 DTG00089002.1 1 23388 DTT00171014.12473.F14.GZ43_361367 DTG00171001.1 1 23389 DTT00514029.12488.G02.GZ43_362590 DTG00514005.1 1 23390 DTT00740010.12466.I08.GZ43_360281 DTG00740003.1 1 23391 DTT00945030.12466.D19.GZ43_360172 DTG00945008.1 1 23392 DTT01169022.12464.N05.GZ43_357997 DTG01169003.1 2 23393 DTT01178009.12510.O21.GZ43_369382 DTG01178002.1 2 23394 DTT01315010.12496.F14.GZ43_364217 DTG01315001.1 2 23395 DTT01503016.12538.M17.GZ43_371544 DTG01503005.1 2 23396 DTT01555018.12538.C07.GZ43_371294 DTG01555002.1 2 23397 DTT01685047.12496.C08.GZ43_364139 DTG01685007.1 2 23398 DTT01764019.12535.C23.GZ43_370158 DTG01764003.1 2 23399 DTT01890015.12482.J06.GZ43_359493 DTG01890004.1 2 23400 DTT02243008.12474.J19.GZ43_361852 DTG02243002.1 3 23401 DTT02367007.12366.P08.GZ43_345738 DTG02367002.1 3 23402 DTT02671007.12464.H22.GZ43_357870 DTG02671002.1 3 23403 DTT02737017.12538.M16.GZ43_371543 DTG02737001.1 3 23404 DTT02850005.12472.G03.GZ43_360996 DTG02850001.1 3 23405 DTT02966016.12510.M14.GZ43_369327 DTG02966003.1 4 23406 DTT03037029.12504.D16.GZ43_365877 DTG03037005.1 4 23407 DTT03150008.12491.P10.GZ43_363966 DTG03150002.1 4 23408 DTT03367008.12542.P19.GZ43_373154 DTG03367003.1 4 23409 DTT03630013.12510.O22.GZ43_369383 DTG03630002.1 4 23410 DTT03881017.12507.O12.GZ43_367289 DTG03881007.1 5 23411 DTT03913023.12459.P24.GZ43_357376 DTG03913005.1 5 23412 DTT03978010.12367.G22.GZ43_346160 DTG03978001.1 5 23413 DTT04070014.12540.H07.GZ43_372182 DTG04070007.1 5 23414 DTT04084010.12542.D19.GZ43_372866 DTG04084001.1 5 23415 DTT04160007.12472.M22.GZ43_361159 DTG04160003.1 5 23416 DTT04302021.12483.O07.GZ43_359998 DTG04302002.1 5 23417 DTT04378009.12368.O11.GZ43_346725 DTG04378001.1 5 23418 DTT04403013.12506.M05.GZ43_366850 DTG04403003.1 5 23419 DTT04414015.12368.D20.GZ43_346470 DTG04414005.1 5 23420 DTT04660017.12507.C03.GZ43_366992 DTG04660003.1 6 23421 DTT04956054.12538.I17.GZ43_371448 DTG04956020.1 6 23422 DTT04970018.12365.F24.GZ43_345370 DTG04970007.1 6 23423 DTT05205007.12459.J12.GZ43_357220 DTG05205001.1 6 23424 DTT05571010.12555.J10.GZ43_373385 DTG05571004.1 7 23425 DTT05650008.12557.L01.GZ43_374192 DTG05650003.1 7 23426 DTT05742029.12560.K10.GZ43_375329 DTG05742002.1 7 23427 DTT06137030.12565.B15.GZ43_398171 DTG06137001.1 8 23428 DTT06161014.12367.F06.GZ43_346120 DTG06161007.1 8 23429 DTT06706019.12467.D10.GZ43_360547 DTG06706003.1 9 23430 DTT06837021.12540.I10.GZ43_372209 DTG06837002.1 9 23431 DTT07040015.12504.E23.GZ43_365908 DTG07040006.1 9 23432 DTT07088009.12565.H01.GZ43_397953 DTG07088001.1 9 23433 DTT07182014.12536.G22.GZ43_370637 DTG07182006.0 10 23434 DTT07405044.12560.B11.GZ43_375114 DTG07405010.1 10 23435 DTT07408020.12466.M02.GZ43_360371 DTG07408005.1 10 23436 DTT07498014.12506.K20.GZ43_366817 DTG07498002.1 10 23437 DTT07600010.12464.H17.GZ43_357865 DTG07600001.1 10 23438 DTT08005024.12475.N21.GZ43_362334 DTG08005009.1 11 23439 DTT08098020.12540.M18.GZ43_372313 DTG08098001.1 11 23440 DTT08167018.12542.F05.GZ43_372900 DTG08167002.1 11 23441 DTT08249022.12498.G15.GZ43_365010 DTG08249008.1 11 23442 DTT08499022.12540.A24.GZ43_372031 DTG08499009.1 12 23443 DTT08514022.12541.L12.GZ43_372667 DTG08514006.1 12 23444 DTT08527013.12489.F09.GZ43_362957 DTG08527005.1 12 23445 DTT08595020.12554.N09.GZ43_376168 DTG08595003.1 12 23446 DTT08711019.12540.C19.GZ43_372074 DTG08711001.1 12 23447 DTT08773020.12559.I12.GZ43_374899 DTG08773008.1 12 23448 DTT08874012.12537.P14.GZ43_371229 DTG08874001.1 12 23449 DTT09387018.12561.P19.GZ43_376610 DTG09387001.1 14 23450 DTT09396022.12489.M11.GZ43_363127 DTG09396001.1 14 23451 DTT09553027.12505.J22.GZ43_366411 DTG09553007.1 14 23452 DTT09604016.12483.J07.GZ43_359878 DTG09604006.1 14 23453 DTT09705033.12536.O22.GZ43_370829 DTG09705006.1 14 23454 DTT09742009.12542.N21.GZ43_373108 DTG09742002.1 15 23455 DTT09753017.12464.L02.GZ43_357946 DTG09753002.1 15 23456 DTT09793019.12464.I04.GZ43_357876 DTG09793004.1 15 23457 DTT09796028.12366.L21.GZ43_345942 DTG09796002.1 15 23458 DTT10221016.12556.C19.GZ43_373610 DTG10221004.1 16 23459 DTT10360040.12475.M20.GZ43_362309 DTG10360016.1 16 23460 DTT10539016.12506.J20.GZ43_366793 DTG10539005.1 17 23461 DTT10564022.12475.H06.GZ43_362175 DTG10564006.1 17 23462 DTT10683041.12542.K21.GZ43_373036 DTG10683007.1 17 23463 DTT10819011.12474.I06.GZ43_361815 DTG10819003.1 17 23464 DTT11363027.12542.C20.GZ43_372843 DTG11363008.1 19 23465 DTT11479018.12506.G24.GZ43_366725 DTG11479007.1 19 23466 DTT11483012.12459.H09.GZ43_357169 DTG11483001.1 19 23467 DTT11548015.12565.C17.GZ43_398204 DTG11548002.1 19 23468 DTT11730017.12535.B09.GZ43_370120 DTG11730004.1 20 23469 DTT11791010.12506.E12.GZ43_366665 DTG11791003.1 20 23470 DTT11864036.12456.H07.GZ43_356003 DTG11864011.1 21 23471 DTT11902028.12490.B06.GZ43_363242 DTG11902009.1 21 23472 DTT11915017.12474.G17.GZ43_361778 DTG11915002.1 21 23473 DTT11966040.12457.L21.GZ43_356497 DTG11966014.1 22 23474 DTT12042027.12459.G01.GZ43_357137 DTG12042005.1 22 23475 DTT12201062.12562.B09.GZ43_375496 DTG12201018.1 X 23476 DTT12470020.12489.A13.GZ43_362841 DTG12470004.1 X 23477 DTT12550009.12504.G01.GZ43_365934 DTG12550003.1 X

TABLE 146 SEQ PROTEIN POLYNTD SEQ DBL TWIST ID SEQ NAME NAME GENE CHROMLOCUS ID 23478 DTP00087033.1 2467.H18.GZ43_360651 DTG00087008.1 1DTL00087012.1 23479 DTP00089029.1 2367.I15.GZ43_346201 DTG00089002.1 1DTL00089002.1 23480 DTP00171023.1 2473.F14.GZ43_361367 DTG00171001.1 1DTL00171013.1 23481 DTP00514038.1 2488.G02.GZ43_362590 DTG00514005.1 1DTL00514023.1 23482 DTP00740019.1 2466.I08.GZ43_360281 DTG00740003.1 1DTL00740006.1 23483 DTP00945039.1 2466.D19.GZ43_360172 DTG00945008.1 123484 DTP01169031.1 2464.N05.GZ43_357997 DTG01169003.1 2 DTL01169014.123485 DTP01178018.1 2510.O21.GZ43_369382 DTG01178002.1 2 DTL01178007.123486 DTP01315019.1 2496.F14.GZ43_364217 DTG01315001.1 2 DTL01315004.123487 DTP01503025.1 2538.M17.GZ43_371544 DTG01503005.1 2 DTL01503007.123488 DTP01555027.1 2538.C07.GZ43_371294 DTG01555002.1 2 DTL01555003.123489 DTP01685056.1 2496.C08.GZ43_364139 DTG01685007.1 2 DTL01685004.123490 DTP01764028.1 2535.C23.GZ43_370158 DTG01764003.1 2 DTL01764005.123491 DTP01890024.1 2482.J06.GZ43_359493 DTG01890004.1 2 DTL01890001.123492 DTP02243017.1 2474.J19.GZ43_361852 DTG02243002.1 3 DTL02243002.123493 DTP02367016.1 2366.P08.GZ43_345738 DTG02367002.1 3 DTL02367004.123494 DTP02671016.1 2464.H22.GZ43_357870 DTG02671002.1 3 DTL02671002.123495 DTP02737026.1 2538.M16.GZ43_371543 DTG02737001.1 3 DTL02737012.123496 DTP02850014.1 2472.G03.GZ43_360996 DTG02850001.1 3 DTL02850004.123497 DTP02966025.1 2510.M14.GZ43_369327 DTG02966003.1 4 DTL02966001.123498 DTP03037038.1 2504.D16.GZ43_365877 DTG03037005.1 4 DTL03030074.123499 DTP03150017.1 2491.P10.GZ43_363966 DTG03150002.1 4 DTL03149001.123500 DTP03367017.1 2542.P19.GZ43_373154 DTG03367003.1 4 DTL03367005.123501 DTP03630022.1 2510.O22.GZ43_369383 DTG03630002.1 4 DTL03630006.123502 DTP03881026.1 2507.O12.GZ43_367289 DTG03881007.1 5 DTL03881006.123503 DTP03913032.1 2459.P24.GZ43_357376 DTG03913005.1 5 DTL03913012.123504 DTP03978019.1 2367.G22.GZ43_346160 DTG03978001.1 5 DTL03978003.123505 DTP04070023.1 2540.H07.GZ43_372182 DTG04070007.1 5 23506DTP04084019.1 2542.D19.GZ43_372866 DTG04084001.1 5 DTL04084001.1 23507DTP04160016.1 2472.M22.GZ43_361159 DTG04160003.1 5 DTL04160003.1 23508DTP04302030.1 2483.O07.GZ43_359998 DTG04302002.1 5 DTL04302006.1 23509DTP04378018.1 2368.O11.GZ43_346725 DTG04378001.1 5 23510 DTP04403022.12506.M05.GZ43_366850 DTG04403003.1 5 DTL04403004.1 23511 DTP04414024.12368.D20.GZ43_346470 DTG04414005.1 5 DTL04414004.1 23512 DTP04660026.12507.C03.GZ43_366992 DTG04660003.1 6 DTL04660002.1 23513 DTP04956063.12538.I17.GZ43_371448 DTG04956020.1 6 DTL04956028.1 23514 DTP04970027.12365.F24.GZ43_345370 DTG04970007.1 6 DTL04970008.1 23515 DTP05205016.12459.J12.GZ43_357220 DTG05205001.1 6 DTL05205002.1 23516 DTP05571019.12555.J10.GZ43_373385 DTG05571004.1 7 DTL05571003.1 23517 DTP05650017.12557.L01.GZ43_374192 DTG05650003.1 7 DTL05650004.1 23518 DTP05742038.12560.K10.GZ43_375329 DTG05742002.1 7 DTL05742003.1 23519 DTP06137039.12565.B15.GZ43_398171 DTG06137001.1 8 DTL06137003.1 23520 DTP06161023.12367.F06.GZ43_346120 DTG06161007.1 8 DTL06161006.1 23521 DTP06706028.12467.D10.GZ43_360547 DTG06706003.1 9 DTL06705001.1 23522 DTP06837030.12540.I10.GZ43_372209 DTG06837002.1 9 DTL06837010.1 23523 DTP07040024.12504.E23.GZ43_365908 DTG07040006.1 9 DTL07040004.1 23524 DTP07088018.12565.H01.GZ43_397953 DTG07088001.1. 9 DTL07088004.1 23525 DTP07405053.12560.B11.GZ43_375114 DTG07405010.1 10 DTL07405034.1 23526 DTP07408029.12466.M02.GZ43_360371 DTG07408005.1 10 DTL07408005.1 23527 DTP07498023.12506.K20.GZ43_366817 DTG07498002.1 10 DTL07498007.1 23528 DTP07600019.12464.H17.GZ43_357865 DTG07600001.1 10 DTL07600004.1 23529 DTP08005033.12475.N21.GZ43_362334 DTG08005009.1 11 DTL08005010.1 23530 DTP08098029.12540.M18.GZ43_372313 DTG08098001.1 11 DTL08098013.1 23531 DTP08167027.12542.F05.GZ43_372900 DTG08167002.1 11 DTL08167003.1 23532 DTP08249031.12498.G15.GZ43_365010 DTG08249008.1 11 DTL08249005.1 23533 DTP08499031.12540.A24.GZ43_372031 DTG08499009.1 12 DTL08499012.1 23534 DTP08514031.12541.L12.GZ43_372667 DTG08514006.1 12 DTL08514015.1 23535 DTP08527022.12489.F09.GZ43_362957 DTG08527005.1 12 DTL08527008.1 23536 DTP08595029.12554.N09.GZ43_376168 DTG08595003.1 12 DTL08595002.1 23537 DTP08711028.12540.C19.GZ43_372074 DTG08711001.1 12 DTL08710003.1 23538 DTP08773029.12559.I12.GZ43_374899 DTG08773008.1 12 DTL08773011.1 23539 DTP08874021.12537.P14.GZ43_371229 DTG08874001.1 12 DTL08874009.1 23540 DTP09387027.12561.P19.GZ43_376610 DTG09387001.1 14 DTL09387002.1 23541 DTP09396031.12489.M11.GZ43_363127 DTG09396001.1 14 DTL09396016.1 23542 DTP09553036.12505.J22.GZ43_366411 DTG09553007.1 14 DTL09553018.1 23543 DTP09604025.12483.J07.GZ43_359878 DTG09604006.1 14 DTL09604010.1 23544 DTP09705042.12536.O22.GZ43_370829 DTG09705006.1 14 DTL09705005.1 23545 DTP09742018.12542.N21.GZ43_373108 DTG09742002.1 15 DTL09742007.1 23546 DTP09753026.12464.L02.GZ43_357946 DTG09753002.1 15 DTL09753011.1 23547 DTP09793028.12464.I04.GZ43_357876 DTG09793004.1 15 DTL09793004.1 23548 DTP09796037.12366.L21.GZ43_345942 DTG09796002.1 15 DTL09796021.1 23549 DTP10221025.12556.C19.GZ43_373610 DTG10221004.1 16 DTL10221002.1 23550 DTP10360049.12475.M20.GZ43_362309 DTG10360016.1 16 DTL10360003.1 23551 DTP10539025.12506.J20.GZ43_366793 DTG10539005.1 17 DTL10539004.1 23552 DTP10564031.12475.H06.GZ43_362175 DTG10564006.1 17 DTL10564006.1 23553 DTP10683050.12542.K21.GZ43_373036 DTG10683007.1 17 DTL10683002.1 23554 DTP10819020.12474.106.GZ43_361815 DTG10819003.1 17 DTL10819002.1 23555 DTP11363036.12542.C20.GZ43_372843 DTG11363008.1 19 DTL11363017.1 23556 DTP11479027.12506.G24.GZ43_366725 DTG11479007.1 19 DTL11479006.1 23557 DTP11483021.12459.H09.GZ43_357169 DTG11483001.1 19 DTL11483006.1 23558 DTP11548024.12565.C17.GZ43_398204 DTG11548002.1 19 DTL11548003.1 23559 DTP11730026.12535.B09.GZ43_370120 DTG11730004.1 20 DTL11730009.1 23560 DTP11791019.12506.E12.GZ43_366665 DTG11791003.1 20 DTL11791005.1 23561 DTP11864045.12456.H07.GZ43_356003 DTG11864011.1 21 DTL11864023.1 23562 DTP11902037.12490.B06.GZ43_363242 DTG11902009.1 21 DTL11902002.1 23563 DTP11915026.12474.G17.GZ43_361778 DTG11915002.1 21 DTL11915001.1 23564 DTP11966049.12457.L21.GZ43_356497 DTG11966014.1 22 DTL11966006.1 23565 DTP12042036.12459.G01.GZ43_357137 DTG12042005.1 22 DTL12042001.1 23566 DTP12201071.12562.B09.GZ43_375496 DTG12201018.1 X DTL12201023.1 23567 DTP12470029.12489.A13.GZ43_3612841 DTG12470004.1 X DTL12470016.1 23568 DTP12550018.12504.G01.GZ43_365934 DTG12550003.1 X DTL12550005.1

A correlation between the polynucleotide used as a query sequence asdescribed above and the corresponding predicted cDNA and proteinsequences is contained in Table 147. Specifically Table 147 provides: 1)the SEQ ID NO of the cDNA (“cDNA SEQ ID”); 2) the cDNA sequence name(“cDNA SEQ NAME”) used as an internal identifier of the sequence; 3) theSEQ ID NO of the protein (“PROTEIN SEQ ID”) encoded by the cDNA sequence4) the sequence name of the protein (“PROTEIN SEQ NAME”) encoded by thecDNA sequence; 5) the SEQ ID NO of the polynucleotide (“POLYNTD SEQ ID”)of SEQ ID NOS: 22001-23267 that maps to the cDNA and protein; and 6) thesequence name (“POLYNTD SEQ NAME”) of the polynucleotide of SEQ ID NOS:22001-23267 that maps to the cDNA and protein.

Through contig and consensus sequence assembly and the use of homologysearching software programs, the sequence information provided hereincan be readily extended to confirm, or confirm a predicted, gene havingthe sequence of the polynucleotides described in the present invention.Further the information obtained can be used to identify the function ofthe gene product of the gene corresponding to the polynucleotidesdescribed herein. While not necessary to the practice of the invention,identification of the function of the corresponding gene, can provideguidance in the design of therapeutics that target the gene to modulateits activity and modulate the cancerous phenotype (e.g., inhibitmetastasis, proliferation, and the like).

Example 95 Results of Public Database Search to Identify Function ofGene Products

SEQ ID NOS:22001-23477 were translated in all three reading frames, andthe nucleotide sequences and translated amino acid sequences used asquery sequences to search for homologous sequences in the GenBank(nucleotide sequences) database. Query and individual sequences werealigned using the TeraBLAST program available from TimeLogic, CrystalBay, Nev. The sequences were masked to various extents to preventsearching of repetitive sequences or poly-A sequences, using theRepeatMasker masking program for masking low complexity as describedabove.

Table 148 (inserted prior to claims) provides the alignment summarieshaving a p value of 1×10e−2 or less indicating substantial homologybetween the sequences of the present invention and those of theindicated public databases. Specifically, Table 148 provides: 1) the SEQID NO (“SEQ ID”) of the query sequence; 2) the sequence name (“SEQNAME”) used as an internal identifier of the query sequence; 3) theaccession number (“ACCESSION”) of the GenBank database entry of thehomologous sequence; 4) a description of the GenBank sequences (“GENBANKDESCRIPTION”); and 5) the score of the similarity of the polynucleotidesequence and the GenBank sequence (“GENBANK SCORE”). The alignmentsprovided in Table 148 are the best available alignment to a DNA sequenceat a time just prior to filing of the present specification. Alsoincorporated by reference is all publicly available informationregarding the sequence listed in Table 147 and their related sequences.The search program and database used for the alignment, as well as thecalculation of the p value are also indicated. Full length sequences orfragments of the polynucleotide sequences can be used as probes andprimers to identify and isolate the full length sequence of thecorresponding polynucleotide. TABLE 147 cDNA cDNA SEQ PROTEIN PROTEINSEQ POLYNTD SEQ ID NAME SEQ ID NAME SEQ ID POLYNTD SEQ NAME 23386DTT00087024.1 1478 DTP00087033.1 963 2467.H18.GZ43_360651 23386DTT00087024.1 1478 DTP00087033.1 33 2505.B05.GZ43_366202 23387DTT00089020.1 1479 DTP00089029.1 213 2367.l15.GZ43_346201 23388DTT00171014.1 1480 DTP00171023.1 1006 2473.F14.GZ43_361367 23388DTT00171014.1 1480 DTP00171023.1 1122 2489.A03.GZ43_362831 23389DTT00514029.1 1481 DTP00514038.1 1113 2488.G02.GZ43_362590 23390DTT00740010.1 1482 DTP00740019.1 952 2466.l08.GZ43_360281 23391DTT00945030.1 1483 DTP00945039.1 945 2466.D19.GZ43_360172 23392DTT01169022.1 1484 DTP01169031.1 482 2540.l17.GZ43_372216 23392DTT01169022.1 1484 DTP01169031.1 914 2464.N05.GZ43_357997 23393DTT01178009.1 1485 DTP01178018.1 113 2510.O21.GZ43_369382 23394DTT01315010.1 1486 DTP01315019.1 1181 2496.F14.GZ43_364217 23395DTT01503016.1 1487 DTP01503025.1 386 2538.M17.GZ43_371544 23396DTT01555018.1 1488 DTP01555027.1 366 2538.C07.GZ43_371294 23396DTT01555018.1 1488 DTP01555027.1 368 2538.D03.GZ43_371314 23396DTT01555018.1 1488 DTP01555027.1 369 2538.D04.GZ43_371315 23397DTT01685047.1 1489 DTP01685056.1 1177 2496.C08.GZ43_364139 23398DTT01764019.1 1490 DTP01764028.1 267 2535.C23.GZ43_370158 23398DTT01764019.1 1490 DTP01764028.1 771 2456.D04.GZ43_355904 23399DTT01890015.1 1491 DTP01890024.1 1087 2482.J06.GZ43_359493 23399DTT01890015.1 1491 DTP01890024.1 1042 2475.B20.GZ43_362045 23417DTT04378009.1 1509 DTP04378018.1 260 2368.O11.GZ43_346725 23418DTT04403013.1 1510 DTP04403022.1 531 2506.M05.GZ43_366850 23419DTT04414015.1 1511 DTP04414024.1 236 2368.D20.GZ43_346470 23420DTT04660017.1 1512 DTP04660026.1 334 2537.D11.GZ43_370938 23420DTT04660017.1 1512 DTP04660026.1 1244 2507.C03.GZ43_366992 23421DTT04956054.1 1513 DTP04956063.1 379 2538.I17.GZ43_371448 23422DTT04970018.1 1514 DTP04970027.1 363 2538.B03.GZ43_371266 23422DTT04970018.1 1514 DTP04970027.1 259 2368.O03.GZ43_346717 23422DTT04970018.1 1514 DTP04970027.1 1101 2483.K02.GZ43_359897 23422DTT04970018.1 1514 DTP04970027.1 134 2365.F24.GZ43_345370 23423DTT05205007.1 1515 DTP05205016.1 880 2459.J12.GZ43_357220 23424DTT05571010.1 1516 DTP05571019.1 586 2555.J10.GZ43_373385 23425DTT05650008.1 1517 DTP05650017.1 644 2557.L01.GZ43_374192 23426DTT05742029.1 1518 DTP05742038.1 721 2560.K10.GZ43_375329 23426DTT05742029.1 1518 DTP05742038.1 126 2365.D10.GZ43_345308 23426DTT05742029.1 1518 DTP05742038.1 756 2561.I19.GZ43_376442 23427DTT06137030.1 1519 DTP06137039.1 419 2565.B15.GZ43_398171 23428DTT06161014.1 1520 DTP06161023.1 205 2367.F06.GZ43_346120 23429DTT06706019.1 1521 DTP06706028.1 967 2467.D10.GZ43_360547 23430DTT06837021.1 1522 DTP06837030.1 465 2540.I10.GZ43_372209 23431DTT07040015.1 1523 DTP07040024.1 10 2504.E23.GZ43_365908 23432DTT07088009.1 1524 DTP07088018.1 170 2366.J06.GZ43_345700 23432DTT07088009.1 1524 DTP07088018.1 429 2565.H01.GZ43_397953 23433DTT07182014.1 DTP07182023.1 306 2536.G22.GZ43_370637 23434 DTT07405044.11525 DTP07405053.1 703 2560.B11.GZ43_375114 23435 DTT07408020.1 1526DTP07408029.1 956 2466.M02.GZ43_360371 23436 DTT07498014.1 1527DTP07498023.1 529 2506.K20.GZ43_366817 23437 DTT07600010.1 1528DTP07600019.1 902 2464.H17.GZ43_357865 23438 DTT08005024.1 1529DTP08005033.1 1046 2475.N21.GZ43_362334 23439 DTT08098020.1 1530DTP08098029.1 485 2540.M18.GZ43_372313 23440 DTT08167018.1 1531DTP08167027.1 152 2365.N12.GZ43_345550 23440 DTT08167018.1 1531DTP08167027.1 544 2542.F05.GZ43_372900 23441 DTT08249022.1 1532DTP08249031.1 1235 2498.G15.GZ43_365010 23442 DTT08499022.1 1533DTP08499031.1 452 2540.A24.GZ43_372031 23443 DTT08514022.1 1534DTP08514031.1 508 2541.L12.GZ43_372667 23444 DTT08527013.1 1535DTP08527022.1 109 2510.N14.GZ43_369351 23444 DTT08527013.1 1535DTP08527022.1 394 2554.A16.GZ43_375863 23444 DTT08527013.1 1535DTP08527022.1 1128 2489.F09.GZ43_362957 23444 DTT08527013.1 1535DTP08527022.1 569 2555.F16.GZ43_373295 23445 DTT08595020.1 1536DTP08595029.1 413 2554.N09.GZ43_376168 23446 DTT08711019.1 1537DTP08711028.1 472 2540.C19.GZ43_372074 23447 DTT08773020.1 1538DTP08773029.1 687 2559.I12.GZ43_374899 23448 DTT08874012.1 1539DTP08874021.1 356 2537.P14.GZ43_371229 23449 DTT09387018.1 1540DTP09387027.1 762 2561.P19.GZ43_376610 23450 DTT09396022.1 1541DTP09396031.1 1140 2489.M11.GZ43_363127 23451 DTT09553027.1 1542DTP09553036.1 54 2505.J22.GZ43_366411 23452 DTT09604016.1 1543DTP09604025.1 1100 2483.J07.GZ43_359878 23453 DTT09705033.1 1544DTP09705042.1 323 2536.O22.GZ43_370829 23454 DTT09742009.1 1545DTP09742018.1 766 2456.B12.GZ43_355864 23454 DTT09742009.1 1545DTP09742018.1 563 2542.N21.GZ43_373108 23455 DTT09753017.1 1546DTP09753026.1 910 2464.L02.GZ43_357946 23456 DTT09793019.1 1547DTP09793028.1 904 2464.I04.GZ43_357876 23457 DTT09796028.1 1548DTP09796037.1 189 2366.L21.GZ43_345942 23458 DTT10221016.1 1549DTP10221025.1 592 2556.C19.GZ43_373610 23459 DTT10360040.1 1550DTP10360049.1 1045 2475.M20.GZ43_362309 23460 DTT10539016.1 1551DTP10539025.1 527 2506.J20.GZ43_366793 23461 DTT10564022.1 1552DTP10564031.1 1035 2475.H06.GZ43_362175 23462 DTT10683041.1 1553DTP10683050.1 561 2542.K21.GZ43_373036 23463 DTT10819011.1 1554DTP10819020.1 796 2457.C19.GZ43_356279 23463 DTT10819011.1 1554DTP10819020.1 143 2365.J14.GZ43_345456 23463 DTT10819011.1 1554DTP10819020.1 1023 2474.I06.GZ43_361815 23464 DTT11363027.1 1555DTP11363036.1 540 2542.C20.GZ43_372843 23465 DTT11479018.1 1556DTP11479027.1 521 2506.G24.GZ43_366725 23466 DTT11483012.1 1557DTP11483021.1 877 2459.H09.GZ43_357169 23467 DTT11548015.1 1558DTP11548024.1 422 2565.C17.GZ43_398204 23468 DTT11730017.1 1559DTP11730026.1 264 2535.B09.GZ43_370120 23469 DTT11791010.1 1560DTP11791019.1 518 2506.E12.GZ43_366665 23470 DTT11864036.1 1561DTP11864045.1 778 2456.H07.GZ43_356003 23471 DTT11902028.1 1562DTP11902037.1 1144 2490.B06.GZ43_363242 23472 DTT11915017.1 1563DTP11915026.1 591 2556.C11.GZ43_373602 23472 DTT11915017.1 1563DTP11915026.1 1021 2474.G17.GZ43_361778 23472 DTT11915017.1 1563DTP11915026.1 1163 2491.C13.GZ43_363657 23473 DTT11966040.1 1564DTP11966049.1 1216 2562.E14.GZ43_375573 23473 DTT11966040.1 1564DTP11966049.1 818 2457.L21.GZ43_356497 23473 DTT11966040.1 1564DTP11966049.1 532 2506.M13.GZ43_366858 23474 DTT12042027.1 1565DTP12042036.1 874 2459.G01.GZ43_357137 23475 DTT12201062.1 1566DTP12201071.1 759 2561.O17.GZ43_376584 23475 DTT12201062.1 1566DTP12201071.1 1207 2562.B09.GZ43_375496 23476 DTT12470020.1 1567DTP12470029.1 1124 2489.A13.GZ43_362841 23476 DTT12470020.1 1567DTP12470029.1 799 2457.D12.GZ43_356296 23476 DTT12470020.1 1567DTP12470029.1 690 2559.J02.GZ43_374913 23476 DTT12470020.1 1567DTP12470029.1 568 2555.E20.GZ43_373275 23477 DTT12550009.1 1568DTP12550018.1 12 2504.G01.GZ43_365934

TABLE 148 GENBANK SEQ ID SEQ NAME ACCESSION GENBANK DESCRIPTION SCORE22006 2504.C08.GZ43_(—) AP000321 gi|4835690|dbj|AP000321.1AP0003211.6E−31 365845 Homo sapiens genomic DNA, chromosome 21q22.1, D21S226-AMLregion, clone: Q82F5, complete sequence 22007 2504.C11.GZ43_(—) AP002938gi|16267134|dbj|AP002938.1AP002938 4.8E−58 365848 Hoplostethus japonicusmitochondrial DNA, complete genome 22009 2504.D16.GZ43_(—) AK023496gi|10435445|dbj|AK023496.1AK023496 0 365877 Homo sapiens cDNA FLJ13434fis, clone PLACE1002578 22010 2504.E23.GZ43_(—) M80340gi|339767|gb|M80340.1HUMTNL12 6.1E−182 365908 Human transposon L1.1 witha base deletion relative to L1.2B resulting in a premature stop codon int 22011 2504.F20.GZ43_(—) AE007289 gi|14524175|gb|AE007289.1AE0072892.1E−98 365929 Sinorhizobium meliloti plasmid pSymA section 95 of 121 ofthe complete plasmid sequence 22017 2504.I13.GZ43_(—) AJ312523gi|12830519|emb|AJ312523.1GGO312523 1.1E−44 365994 Gorilla gorillagorilla Xq13.3 chromosome non-coding sequence, isolate G167W 220312504.O12.GZ43_(—) AF342020 gi|12961941|gb|AF342020.1AF342020 1.1E−90366137 Sclerotinia sclerotiorum strain LES-1 28S ribosomal RNA gene,partial sequence; intergenic spacer 22033 2505.B05.GZ43_(—) U93571gi|2072968|gb|U93571.1HSU93571 1.1E−226 366202 Human L1 element L1.24p40 gene, complete cds 22037 2505.C17.GZ43_(—) AJ325713gi|158701107|emb|AJ325713.1HSA325713 1.4E−21 366238 Homo sapiens genomicsequence surrounding NotI site, clone NB1-110S 22040 2505.D03.GZ43_(—)AJ224335 gi|3413799|emb|AJ224335.1HSAJ4335 5.2E−71 366248 Homo sapienmRNA for putative secretory protein, hBET3 22043 2505.E15.GZ43_(—)AB030001 gi|7416074|dbj|AB030001.1AB030001 8.1E−55 366284 Homo sapiensgene for SGRF, complete cds 22046 2505.G16.GZ43_(—) AE005683gi|13421186|gb|AE005683.1AE005683 3.6E−63 366333 Caulobacter crescentussection 9 of 359 of the complete genome 22048 2505.I04.GZ43_(—) AF255613gi|8925326|gb|AF255613.1AF255613 7.9E−73 366369 Homo sapiensteratoma-associated tyrosine kinase (TAPK) gene, exons 1 through 6 andpartial cds 22063 2505.O09.GZ43_(—) AF053644gi|3598786|gb|AF053644.1HSCSE1G2 9.4E−45 366518 Homo sapiens cellularapoptosis susceptibility protein (CSE1) gene, exon 2 220722510.C10.GZ43_(—) AB002353 gi|2224650|dbj|AB002353.1AB002353 1.4E−71369083 Human mRNA for KIAA0355 gene, complete cds 220782510.G06.GZ43_(—) AF084935 gi|3603422|gb|AF084935.1AF084935 8.9E−24369175 Homo sapiens galactokinase (GALK1) gene, partial cds 220892510.J11.GZ43_(—) AK024617 gi|10436933|dbj|AK024617.1AK024617 0 369252Homo sapiens cDNA: FLJ20964 fis, clone ADSH00902 22102 2510.L21.GZ43_(—)AK023677 gi|10435673|dbj|AK023677.1AK023677 1.2E−90 369310 Homo sapienscDNA FLJ13615 fis, clone PLACE1010896, weakly similar to NUF1 PROTEIN22109 2510.N14.GZ43_(—) AF271388 gi|8515842|gb|AF271388.1AF271388 0369351 Homo sapiens CMP-N-acetylneuraminic acid synthase mRNA, completecds 22115 2510.O23.GZ43_(—) AF113169 gi|4164598|gb|AF113169.1AF1131692.2E−39 369384 Homo sapiens glandular kallikrein enhancer region,complete sequence 22124 2365.C20.GZ43_(—) AF069489gi|3560568|gb|AF069489.1HSPDE4A3 6.6E−24 345294 Homo sapiens cAMPspecific phosphodiesterase 4A varient pde46 (PDE4A) gene, exons 2through 13 and 22134 2365.F24.GZ43_(—) AK012908gi|12849956|dbj|AK012908.1AK012908 2.9E−224 345370 Mus musculus 10, 11days embryo cDNA, RIKEN full-length enriched library, clone: 2810046L04,full 22143 2365.J14.GZ43_(—) BC007999 gi|14124949|gb|BC007999.1BC0079994.4E−56 345456 Homo sapiens, hypothetical protein FLJ10759, clone MGC:15757 IMAGE: 3357436, mRNA, complete cds 22152 2365.N12.GZ43_(—) U20391gi|1483626|gb|U20391.1HSU20391 3.9E−41 345550 Human folate reeceptor(FOLR1) gene, complete cds 22162 2366.E03.GZ43_(—) AB025285gi|5917586|dbj|AB025285.1AB025285 4.3E−30 345647 Homo sapiens c-ERBB-2gene, exons 1′, 2′, 3′, 4′ 22163 2366.J03.GZ43_(—) M15885gi|338414|gb|M15885.1HUMSPP Human 1.1E−68 345652 prostate secretedseminal plasma protein mRNA, complete cds 22170 2366.J06.GZ43_(—)AF326517 gi|15080738|gb|AF326517.1AF326517 0 345700 Abies grandis pinenesynthase gene, partial cds 22182 2366.K13.GZ43_(—) U27333gi|967202|gb|U27333.1HSU27333 Human 2.5E−44 345813 alpha(1,3)fucosyltransferase (FUT6) mRNA, major transcript I, complete cds 221892366.L21.GZ43_(—) AF272390 gi|8705239|gb|AF272390.1AF272390 1.4E−290345942 Homo sapiens mysoin 5c (MYO5C) mRNA, complete cds 221952367.B10.GZ43_(—) AJ279823 gi|11932035|emb|AJ279823.1ASF279823 1.4E−231346028 Ascovirus SfA V1b partial pol gene for DNA polymerase,Pol2-Pol3-Pol1 fragment 22198 2367.C12.GZ43_(—) BC014669gi|15779227|gb|BC014669.1BC014669 2.9E−57 346054 Homo sapiens, cloneIMAGE: 4849317, mRNA, partial cds 22200 2367.D18.GZ43_(—) AE008517gi|15459138|gb|AE008517.1AE008517 1.4E−34 346084 Streptococcuspneumoniae R6 section 133 of 184 of the complete genome 222052367.F06.GZ43_(—) AJ330464 gi|15874882|emb|AJ330464.1HSA330464 3.1E−100346120 Homo sapiens genomic sequence surrounding NotI site, cloneNR1-IL7C 22206 2367.F13.GZ43_3 AY035075 gi|14334803|gb|AY035075.1Arabidopsis 4.1E−229 346127 thaliana putative H+-transporting ATPase(AT4g30190) mRNA, complete cds 22208 2367.G13.GZ43_(—) AK025355gi|10437854|dbj|AK025355.1AK025355 1.8E−58 346151 Homo sapiens cDNA:FLJ21702 fis, clone COL09874 22209 2367.G17.GZ43_(—) AK000293gi|7020278|dbj|AK000293.1AK000293 4.4E−34 346155 Homo sapiens cDNAFLJ20286 fis, clone HEP04358 22210 2367.G20.GZ43_(—) AL137592gi|6808332|emb|AL137592.1HSM802347 1.6E−60 346158 Homo sapiens mRNA;cDNA DKFZp434L0610 (from clone DKFZp434L0610); partial cds 222112367.G22.GZ43_(—) BC015529 gi|15930193|gb|BC015529.1BC015529 9.7E−60346160 Homo sapiens, Similar to ribose 5- phosphate isomerase A, cloneMGC: 9441 IMAGE: 3904718, mRNA, comp 22213 2367.I15.GZ43_(—) AF324172gi|12958747|gb|AF324172.1AF324172 4.8E−65 346201 Dictyophora indusiatastrain ASI 32001 internal transcribed spacer 1, partial sequence; 5.8Sribo 22217 2367.K24.GZ43_(—) AF009251 gi|2352833|gb|AF009251.1CLCN6HUM053.8E−62 346258 Homo sapiens putative chloride channel gene (CLCN6), exon6 22219 2367.M06.GZ43_(—) AF178322 gi|13344845|gb|AF178322.1AF1783221.5E−43 346288 Schmidtea mediterranea cytochrome oxidase C subunit I(COI) gene, partial cds; mitochondrial gene 22220 2367.M14.GZ43_(—)AK026286 gi|10439097|dbj|AK026286.1AK026286   1E−300 346296 Homo sapienscDNA: FLJ22633 fis, clone HSI06502 22221 2367.M16.GZ43_(—) AF368920gi|14039926|gb|AF368920.1AF368920 1.6E−83 346298 Caenorhabditis elegansvoltage-dependent calcium channel alpha13 subunit (cca-1) mRNA, completec 22224 2367.N16.GZ43_(—) Z78727 gi|1508005|emb|Z78727.1HSPA15B9 1.3E−37346322 H. sapiens flow-sorted chromosome 6 HindIII fragment, SC6pA15B922231 2368.B18.GZ43_(—) AK000293 gi|7020278|dbj|AK000293.1AK000293  5E−34 346420 Homo sapiens cDNA FLJ20286 fis, clone HEP04358 222352368.D08.GZ43_(—) AJ276936 gi|12214232|emb|AJ276936.1NME276936 0 346458Neisseria meningitidis partial tbpB gene for transferrin binding proteinB subunit, allele 66, 22245 2368.I04.GZ43_(—) AY042191gi|15546022|gb|AY042191.1 Mus 3.1E−26 346574 musculus RF-amide Gprotein-coupled receptor (MrgA1) mRNA, complete cds 222492368.K21.GZ43_(—) AJ310931 gi|15718363|emb|AJ310931.1HSA310931   7E−55346639 Homo sapiens mRNA for myosin heavy chain 22252 2368.M19.GZ43_(—)AK025595 gi|10438161|dbj|AK025595.1AK025595 4.7E−21 346685 Homo sapienscDNA: FLJ21942 fis, clone HEP04527 22257 2368.N15.GZ43_(—) AK014328gi|12852104|dbj|AK014328.1AK014328 3.1E−103 346705 Mus musculus 14, 17days embryo head cDNA, RIKEN full-length enriched library, clone:3230401M21, 22258 2368.N23.GZ43_(—) AL391428gi|9864373|emb|AL391428.1AL391428 4.8E−28 346713 Human DNA sequence fromclone RP11- 60P19 on chromosome 1, complete sequence [Homo sapiens]22259 2368.O03.GZ43_(—) AK012908 gi|12849956|dbj|AK012908.1AK0129082.1E−227 346717 Mus musculus 10, 11 days embryo cDNA, RIKEN full-lengthenriched library, clone: 2810046L04, full 22260 2368.O11.GZ43_(—)AF102129 gi|5922722|gb|AF102129.1AF102129 2.5E−103 346725 Rattusnorvegicus KPL2 (Kp12) mRNA, complete cds 22264 2535.B09.GZ43_(—)AF292648 gi|12656358|gb|AF292648.1AF292648   2E−39 370120 Mus musculuszinc finger 202 ml (Znf202) mRNA, complete cds 22267 2535.C23.GZ43_(—)AF307053 gi|12018057|gb|AF307053.1AF307053 0 370158 Thermococcuslitoralis sugar kinase, trehalose/maltose binding protein (malE),trehalose/maltose 22269 2535.F05.GZ43_(—) AF367433gi|14486704|gb|AF367433.1AF367433 3.8E−38 370212 Lotus japonicusphosphatidylinositol transfer-like protein III (LjPLP-III) mRNA,complete cds 22276 2535.L03.GZ43_(—) AK000099gi|7019966|dbj|AK000099.1AK000099 7.1E−52 370354 Homo sapiens cDNAFLJ20092 fis, clone COL04215 22280 2535.O07.GZ43_(—) BC008425gi|14250051|gb|BC008425.1BC008425 3.8E−34 370430 Homo sapiens, cloneMGC: 14582 IMAGE: 4246114, mRNA, complete cds 22282 2535.P02.GZ43_(—)NM_024074 gi|13129059|ref|NM_024074.1 Homo 2.4E−23 370449 sapienshypothetical protein MGC3169 (MGC3169), mRNA 22292 2536.A22.GZ43_(—)AF310311 gi|13517433|gb|AF310311.1AF310311 0 370493 Homo sapiens isolateNigeria 9 membrane protein CH1 gene, partial cds 22297 2536.D17.GZ43_(—)AF015148 gi|2353128|gb|AF015148.1AF015148 1.6E−46 370560 Homo sapiensclone HS19.2 Alu-Ya5 sequence 22303 2536.G05.GZ43_(—) AF045605gi|3228525|gb|AF045605.1AF045605 6.2E−77 370620 Homo sapiens germlinechromosome 11, 11q13 region 22305 2536.G21.GZ43_(—) AK026490gi|10439363|dbj|AK026490.1AK026490 3.5E−143 370636 Homo sapiens cDNA:FLJ22837 fis, clone KAIA4417 22306 2536.G22.GZ43_(—) NC_002707gi|13540758|ref|NC_002707.1 Anguilla 2.3E−39 370637 japonicamitochondrion, complete genome 22309 2536.I05.GZ43_(—) AK000099gi|7019966|dbj|AK000099.1AK000099 3.4E−63 370668 Homo sapiens cDNAFLJ20092 fis, clone COL04215 22310 2536.I15.GZ43_(—) AB013897gi|6177784|dbj|AB013897.1AB013897 5.1E−53 370678 Homo sapiens mRNA forHKR1, partial cds 22313 2536.J11.GZ43_(—) AK023448gi|10435386|dbj|AK023448.1AK023448 0 370698 Homo sapiens cDNA FLJ13386fis, clone PLACE1001104, weakly similar to MYOSIN HEAVY CHAIN, NON-MU22314 2536.K12.GZ43_(—) U14573 gi|551542|gb|U14573.1HSU14573   1E−96370723 ***ALU WARNING: Human Alu-Sq subfamily consensus sequence 223192536.N05.GZ43_(—) AK001347 gi|7022548|dbj|AK001347.1AK001347 6.7E−43370788 Homo sapiens cDNA FLJ10485 fis, clone NT2RP2000195 223202536.N20.GZ43_(—) Y15724 gi|3021395|emb|Y15724.1HSSERCA1 1.9E−27 370803Homo sapiens SERCA3 gene, exons 1-7 (and joined CDS) 223302537.B07.GZ43_(—) X69516 gi|288876|emb|X69516.1HSFOLA 2.8E−60 370886 H.sapiens gene for folate receptor 22334 2537.D11.GZ43_(—) NM_025080gi|13376633|ref|NM_025080.1 Homo 8.7E−289 370938 sapiens hypotheticalprotein FLJ22316 (FLJ22316), mRNA 22338 2537.G05.GZ43_(—) L04193gi|187144|gb|L04193.1HUMLIMGP 7.4E−52 371004 Human lens membrane protein(mp19) gene, exon 11 22341 2537.I03.GZ43_(—) Z78727gi|1508005|emb|Z78727.1HSPA15B9 1.7E−37 371050 H. sapiens flow-sortedchromosome 6 HindIII fragment, SC6pA15B9 22345 2537.K17.GZ43_(—)AL603947 gi|15384818|emb|AL603947.1UMA0006 9.3E−76 371112 Ustilagomaydis gene for predicted plasmamembrane-ATPase 22350 2537.N23.GZ43_(—)AF242865 gi|985870|gb|AF242865.1AF242862S4 2.4E−30 371190 Homo sapienscoxsackie virus and adenovirus receptor (CXADR) gene, exon 7 andcomplete cds 22352 2537.O05.GZ43_(—) AB060827gi|13874462|dbj|AB060827.1AB060827 2.2E−24 371196 Macaca fascicularisbrain cDNA clone: QtrA-10256, full insert sequence 223562537.P14.GZ43_(—) AK026442 gi|10439307|dbj|AK026442.1AK026442 6.3E−256371229 Homo sapiens cDNA: FLJ22789 fis, clone KAIA2171 223612538.A10.GZ43_(—) AK001432 gi|7022685|dbj|AK001432.1AK001432 1.9E−52371249 Homo sapiens cDNA FLJ10570 fis, clone NT2RP2003117 223632538.B03.GZ43_(—) AK013900 gi|1285449|dbj|AK013900.1AK013900 1.2E−201371266 Mus musculus 12 days embryo head cDNA, RIKEN full-length enrichedlibrary, clone: 3010026L22, ful 22366 2538.C07.GZ43_(—) AK022973gi|10434673|dbj|AK022973.1AK022973 0 371294 Homo sapiens cDNA FLJ12911fis, clone NT2RP2004425, highly similar to Mus musculus axotrophin mR22367 2538.C14.GZ43_(—) M87914 gi|174891|gb|M87914.1HUMALNE461   2E−89371301 Human carcinoma cell-derived Alu RNA transcript, clone NE46122368 2538.D03.GZ43_(—) AK022973 gi|10434673|dbj|AK022973.1AK0229734.3E−275 371314 Homo sapiens cDNA FLJ12911 fis, clone NT2RP2004425,highly similar to Mus musculus axotrophin mR 22369 2538.D04.GZ43_(—)AK022973 gi|10434673|dbj|AK022973.1AK022973 1.3E−287 371315 Homo sapienscDNA FLJ12911 fis, clone NT2RP2004425, highly similar to Mus musculusaxotrophin mR 22371 2538.E01.GZ43_(—) AF074397gi|3916231|gb|AF074397.1AF074397   4E−40 371336 Homo sapiensanti-mullerian hormone type II receptor (AMHR2) gene, promoter regionand partial cds 22374 2538.F03.GZ43_(—) L34639gi|598203|gb|L34639.1HUMPECAM09 1.5E−43 371362 Homo sapiensplatelet/endothelial cell adhesion molecule-1 (PECAM-1) gene, exon 622375 2538.H02.GZ43_(—) AF220173 gi|9651700|gb|AF220173.1AF220172S22.5E−39 371409 Homo sapiens acid ceramidase (ASAH) gene, exons 2 through4 22379 2538.I17.GZ43_(—) AF050179 gi|3319283|gb|AE050179.1AF0501794.9E−41 371448 Homo sapiens CENP-C binding protein (DAXX) mRNA, completecds 22380 2538.J10.GZ43_(—) AY035075 gi|14334803|gb|AY035075.1Arabidopsis 3.5E−245 371465 thaliana putative H+-transporting ATPase(AT4g30190) mRNA, complete cds 22381 2538.K17.GZ43_(—) AK022749gi|10434332|dbj|AK022749.1AK022749 1.5E−31 371496 Homo sapiens cDNAFLJ12687 fis, clone NT2RM4002532, weakly similar to PROTEIN HOM1 223852538.M16.GZ4_(—) AF375410 gi|14030638|gb|AF375410.1AF375410 1.9E−53371543 Arabidopsis thaliana At2g43970/F6E13.10 gene, complete cds 223862538.M17.GZ43_(—) AK025473 gi|10437996|dbj|AK025473.1AK025473 3.2E−282371544 Homo sapiens cDNA: FLJ21820 fis, clone HEP01232 223892538.P16.GZ43_(—) AK026286 gi|10439097|dbj|AK026286.1AK026286 0 371615Homo sapiens cDNA: FLJ22633 fis, clone HSI06502 22391 2554.A06.GZ43_(—)AK001324 gi|7022509|dbj|AK001324.1AK001324   4E−44 375853 Homo sapienscDNA FLJ10462 fis, clone NT2RP1001494, weakly similar to MALE STERILITYPROTEIN 2 22394 2554.A16.GZ43_(—) AF271388gi|8515842|gb|AF271388.1AF271388 0 375863 Homo sapiensCMP-N-acetylneuraminic acid synthase mRNA, complete cds 224062554.I15.GZ43 AY050376 gi|15215695|gb|AY050376.1 Arabidopsis 8.8E−27376054 thaliana AT3g16950/K14A17_7 mRNA, complete cds 224152554.P16.GZ43_(—) AK022368 gi|10433751|dbj|AK022368.1AK022368 6.7E−46376223 Homo sapiens cDNA FLJ12306 fis, clone MAMMA 1001907 224182565.B13.GZ43_(—) AL050012 gi|4884261|emb|AL050012.1HSM800354   1E−44398139 Homo sapiens mRNA; cDNA DKFZp564K133 (from clone DKFZp564K133)22419 2565.B15.GZ43_(—) AY049285 gi|15146287|gb|AY049285.1 Arabidopsis2.1E−62 398171 thaliana AT3g58570/F14P22_160 mRNA, complete cds 224222565.C17.GZ43_(—) M24543 gi|341200|gb|M24543.1 HUMPSANTIG 2.5E−49 398204Human prostate-specific antigen (PA) gene, complete cds 224232565.D06.GZ43_(—) AF331321 gi|13095271|gb|AF331321.1AF331321 4.7E−30398029 HIV1 isolate T7C44 from the Netherlands nonfunctional polpolyprotein gene, partial sequence 22428 2565.G20.GZ43_(—) AJ276936gi|1221232|emb|AJ276936.1NME276936 0 398256 Neisseria meningitidispartial tbpB gene for transferrin binding protein B subunit, allele 66,22429 2565.H01.GZ43_(—) AF326517 gi|15080738|gb|AF326517.1AF326517  1E−300 397953 Abies grandis pinene synthase gene, partial cds 224332565.I22.GZ43_(—) AK001926 gi|7023492|dbj|AK001926.1AK001926 8.9E−295398290 Homo sapiens cDNA FLJ11064 fis, clone PLACE1004824 224422565.M14.GZ43_(—) AF275699 gi|12275949|gb|AF275699.1AF275699 1.4E−21398166 Unidentified Hailaer soda lake bacterium F16 16S ribosomal RNAgene, partial sequence 22447 2565.O07.GZ43_(—) AK024752gi|10437118|dbj|AK024752.1AK024752 4.3E−51 398056 Homo sapiens cDNA:FLJ21099 fis, clone CAS04610 22452 2540.A24.GZ43_(—) Z69920gi|1217632|emb|Z69920.1HS91K3D 1.1E−41 372031 Human DNA sequence fromcosmid 91K3, Huntington's Disease Region, chromosome 4p16.3 224632540.H07.GZ43_(—) AE008025 gi|15155943|gb|AE008025.1AE008025 1.7E−40372182 Agrobacterium tumefaciens strain C58 circular chromosome, section83 of 254 of the complete seque 22465 2540.I10.GZ43_(—) AK000658gi|7020892|dbj|AK000658.1AK000658 1.3E−53 372209 Homo sapiens cDNAFLJ20651 fis, clone KAT01814 22468 2540.M22.GZ43_(—) AF375597gi|14150816|gb|AF375597.1AF375596S2 0 372317 Mus musculus medium andshort chain L-3- hydroxyacyl-Coenzyme A dehydrogenase (Mschad) gene, exo22472 2540.C19.GZ43_(—) AB019559 gi|4579750|dbj|AB019559.1AB0195593.1E−24 372074 Sus scrofa mRNA for 130 kDa regulatory subunit of myosinphosphatase, partial cds 22477 2540.F15.GZ43_(—) AY016428gi|13891961|gb|AY016428.1 Plasmodium 2.2E−33 372142 falciparum isolateFas 30-6-7 apical membrane antigen-1 (AMA-1) gene, partial cds 224852540.M18.GZ43_(—) AJ331177 gi|15875595|emb|AJ331177.1HSA331177 7.7E−237372313 Homo sapiens genomic sequence surrounding NotI site, cloneNL1-ZF18RS 22507 2541.L08.GZ43_(—) BC003673gi|13277537|gb|BC003673.1BC003673 2.6E−53 372663 Homo sapiens, protamine1, clone MGC: 12307 IMAGE: 3935638, mRNA, complete cds 225082541.L12.GZ43_(—) AJ297708 gi|12055486|emb|AJ297708.1RNO297708 9.4E−45372667 Rattus norvegicus RT6 gene for T cell differentiation markerRT6.2, exons 1-8 22514 2506.C15.GZ43_(—) AE007488gi|14973493|gb|AE007488.1AE007488 1.4E−287 366620 Streptococcuspneumoniae TIGR4 section 171 of 194 of the complete genome 225192506.E18.GZ4_(—) AK025164 gi|10437625|dbj|AK025164.1AK025164 0 366671Homo sapiens cDNA: FLJ21511 fis, clone COL05748 22521 2506.G24.GZ43_(—)AY030962 gi|13736961|gb|AY030962.1 HIV-1 isolate, 9.1E−233 366725NC3964-1999 from USA pol polyprotein (pol) gene, partial cds 225272506.J20.GZ43_(—) AF152924 gi|5453323|gb|AF152924.1AF152924 Mus 2.3E−79366793 musculus syntaxin4-interacting protein synip mRNA, complete cds22528 2506.J22.GZ43_(—) AK000169 gi|7020080|dbj|AK000169.1AK0001691.8E−99 366795 Homo sapiens cDNA FLJ20162 fis, clone COL09280 225312506.M05.GZ43_(—) AE007580 gi|15023517|gb|AE007580.1AE007580 2.1E−217366850 Clostridium acetobutylicum ATCC824 section 68 of 356 of thecomplete genome 22534 2506.P07.GZ43_(—) AF035442gi|3142369|gb|AF035442.1AF035442   1E−44 366924 Homo sapiens VAV-likeprotein mRNA, partial cds 22540 2542.C20.GZ43_(—) AE007424gi|14972724|gb|AE007424.1AE007424 2.3E−42 372843 Streptococcuspneumoniae TIGR4 section 107 of 194 of the complete genome 225432542.D19.GZ43_(—) BC008333 gi|14249906|gb|BC008333.1BC008333 5.3E−284372866 Homo sapiens, clone IMAGE: 3506145, mRNA, partial cds 225442542.F05.GZ43_(—) AK024179 gi|10436495|dbj|AK024179.1AK024179 2.4E−41372900 Homo sapiens cDNA FLJ14117 fis, clone MAMMA1001785 225532542.M09.GZ43_(—) AK022973 gi|1043673|dbj|AK022973.1AK022973 5.8E−243373072 Homo sapiens cDNA FLJ12911 fis, clone NT2RP2004425, highlysimilar to Mus musculus axotrophin mR 22557 2542.P19.GZ43_(—) AK025164gi|10437625|dbj|AK025164.1AK025164 0 373154 Homo sapiens cDNA: FLJ21511fis, clone COL05748 22562 2542.M24.GZ43_(—) AK022173gi|10433509|dbj|AK022173.1AK022173 1.2E−284 373087 Homo sapiens cDNAFLJ12111 fis, clone MAMMA1000025 22563 2542.N21.GZ43_(—) AF025409gi|2582414|gb|AF025409.1AF025409   2E−70 373108 Homo sapiens zinctransporter 4 (ZNT4) mRNA, complete cds 22567 2555.D22.GZ43_(—)AL1576971 gi|11121002|emb|AL157697.11AL157697 1.1E−87 373253 Human DNAsequence from clone RP5- 1092C14 on chromosome 6, complete sequence[Homo sapiens] 22568 2555.E20.GZ43_(—) AK026618gi|10439509|dbj|AK026618.1AK026618 0 373275 Homo sapiens cDNA: FLJ22965fis, clone KAT10418 22569 2555.F16.GZ43_(—) AF271388gi|8515842|gb|AF271388.1AF271388 0 373295 Homo sapiensCMP-N-acetylneuraminic acid synthase mRNA, complete cds 225742555.K17.GZ43_(—) AK026686 gi|10439593|dbj|AK026686.1AK026686 1.8E−23373416 Homo sapiens cDNA: FLJ23033 fis, clone LNG02005 225782555.P22.GZ43_(—) AF087913 gi|5081331|gb|AF087913.1AF087913 5.8E−74373541 Human endogenous retrovirus HERV-P- T47D 22579 2555.A11.GZ43_(—)NC_000957 gi|11497445|ref|NC_000957.1 Borrelia 1.3E−57 373170burgdorferi plasmid 1p5, complete sequence 22585 2555.I12.GZ43_(—)AJ276936 gi|12214232|emb|AJ276936.1NME276936 1.6E−237 373363 Neisseriameningitidis partial tbpB gene for transferrin binding protein Bsubunit, allele 66, 22589 2556.A02.GZ43_(—) AE007289gi|14524175|gb|AE007289.1AE007289   2E−55 373545 Sinorhizobium melilotiplasmid pSymA section 95 of 121 of the complete plasmid sequence 225912556.C11.GZ43_(—) AY039252 gi|15418981|gb|AY039252.1 Macaca 3.1E−29373602 mulatta immunoglobulin alpha heavy chain constant region (IgA)gene, IgA-C.II allele, partial cds 22602 2556.H15.GZ43_(—) AK021966gi|10433275|dbj|AK021966.1AK021966 1.6E−70 373726 Homo sapiens cDNAFLJ11904 fis, clone HEMBB1000048 22620 2557.B22.GZ43_(—) AB071392gi|15721873|dbj|AB071392.1AB071392 1.2E−25 373973 Expression vectorpAQ-EX1 DNA, complete sequence 22627 2557.J14.GZ43_(—) AK023721gi|10435737|dbj|AK023721.1AK023721 1.6E−209 374157 Homo sapiens cDNAFLJ13659 fis, clone PLACE1011576, moderately similar to Human Kruppelrelated 22635 2557.N14.GZ43_(—) AB013897gi|6177784|dbj|AB013897.1AB013897   1E−44 374253 Homo sapiens mRNA forHKR1, partial cds 22648 2558.B24.GZ43_(—) AB064318gi|14595115|dbj|AB064318.1AB064318 4.6E−28 374359 Comamonas testosteronigene for 16S rRNA, partial sequence 22657 2558.G07.GZ43_(—) M92069gi|337698|gb|M92069.1HUMRTVLC 6.7E−46 374462 Human retrovirus-likesequence-isoleucine c (RTVL-Ic) gene, Alu repeats 226612558.H17.GZ43_(—) AK023812 gi|10435860|dbj|AK023812.1AK023812 5.2E−31374496 Homo sapiens cDNA FLJ13750 fis, clone PLACE3000331 226622558.J01.GZ43_(—) AK023448 gi|10435386|dbj|AK023448.1AK023448 4.8E−278374528 Homo sapiens cDNA FLJ13386 fis, clone PLACE1001104, weaklysimilar to MYOSIN HEAVY CHAIN, NON-MU 22666 2558.K02.GZ43_(—) U14573gi|551542|gb|U14573.1HSU14573 1.3E−62 374553 ***ALU WARNING: HumanAlu-Sq subfamily consensus sequence 22683 2559.D05.GZ43_(—) AF338713gi|14039582|gb|AF338713.1AF338713   4E−297 374772 Casuarius casuariusmitochondrion, partial genome 22687 2559.I12.GZ43_(—) AY036096gi|14486435|gb|AY036096.1 HIV-1 isolate 1.4E−41 374899 L2Q2P fromBelgium reverse transcriptase (pol) gene, partial cds 226902559.J02.GZ43_(—) AK026618 gi|10439509|dbj|AK026618.1AK026618 0 374913Homo sapiens cDNA: FLJ22965 fis, clone KAT10418 22692 2559.K12.GZ43_(—)Z96776 gi|2181853|emb|Z96776.1HS9QT023 5.1E−52 374947 H. sapienstelomeric DNA sequence, clone 9QTEL023, read 9QTELOO023.seq 226942559.L09.GZ43_(—) AE007426 gi|14972746|gb|AE007426.1AE007426 8.1E−21374968 Streptococcus pneumoniae TIGR4 section 109 of 194 of the completegenome 22696 2559.M21.GZ43_(—) AJ414564gi|15990852|emb|AJ414564.1HSA414564 9.2E−30 375004 Homo sapiens mRNA forconnexin40.1 (CX40.1 gene) 22698 2559.N13.GZ43_(—) AL137330gi|6807822|emp|AL137330.1HSM802010 4.1E−47 375020 Homo sapiens mRNA;cDNA DKFZp434F0272 (from clone DKFZp434F0272) 22714 2560.H01.GZ43_(—)U14567 gi|551536|gb|U14567.1HSU14567 2.7E−42 375248 ***ALU WARNING:Human Alu-J subfamily consensus sequence 22719 2560.K02.GZ43_(—)AF178754.3 gi|7770069|gb|AF178754.3AF178754 3.1E−51 375321 Homo sapienslithium-sensitive myoinositol monophosphatase A1 (IMPA1) gene, promoterregion and p 22720 2560.K08.GZ43_(—) AK009327gi|12844057|dbj|AK009327.1AK009327 6.3E−80 375327 Mus musculus adultmale tongue cDNA, RIKEN full-length enriched library, clone: 2310012P17,full 22721 2560.K10.GZ43_(—) AF344987 gi|13448249|gb|AF344987.1AF344987  1E−300 375329 Hepatitis C virus isolate RDpostSC1c2 polyprotein gene,partial cds 22729 2560.O08.GZ43_(—) AY037285gi|15982643|gb|AY037285.1AY037284S2 5.2E−54 375423 HIV-1 from Cameroonvpu protein (vpu) and envelope glycoprotein (env) genes, complete cds;and 22732 2561.B03.GZ43_(—) AF035968.2 gi|8714504|gb|AF035968.2AF0359683.9E−32 376258 Home sapiens integrin alpha 2 (ITGA2) gene, ITGA2-1allele, exons 6-9, and partial, cds 22733 2561.B12.GZ43_(—) AP000276gi|4835645|dbj|AP000276.1AP000276 1.9E−27 376267 Homo sapiens genomicDNA, chromosome 21q22.1, D21S226-AML region, clone: 55A9, completesequence 22750 2561.M09.GZ43_(—) AF052684gi|2995716|gb|AF052684.1HSPRACAD2 4.1E−41 376528 Homo sapiensprotocadherin 43 gene, exon 2 22753 2561.E22.GZ43_(—) AF132952gi|4680674|gb|AF132952.1AF132952   3E−41 376349 Homo sapiens CGI-18protein mRNA, complete cds 22754 2561.G20.GZ43_(—) U14573gi|551542|gb|U14573.1HSU14573 1.5E−71 376395 ***ALU WARNING: HumanAlu-Sq subfamily consensus sequence 22755 2561.H17.GZ43_(—) AF052685gi|2995717|gb|AF052685.1HSPRCAD3 2.1E−24 376416 Homo sapiensprotocadherin 43 gene, exon 3, exon 4, and complete cds 227562561.I19.GZ43_(—) AF344987 gi|13448249|gb|AF344987.1AF344987 3.2E−201376442 Hepatitis C virus isolate RDpostsSC1c2 polyprotein gene, partialcds 22761 2561.P16.GZ43_(—) Z78727 gi|1508005|emp|Z78727.1HSPA15B91.6E−37 376607 H. sapiens flow-sorted chromosome 6 HindIII fragment,SC6pA15B9 22762 2561.P19.GZ43_(—) U66535 gi|2270915|gb|U66535.1HSITGBF078.6E−41 376610 Human beta4-integrin (ITGB4) gene, exons 19, 20, 21, 22,23, 24 and 25 22763 2561.P23.GZ43_(—) AF167458gi|6467463|gb|AF167458.1HSDSRPKR04   1E−22 376614 Homo sapiens doublestranded RNA activated protein kinase (PKR) gene, intron 1 227712456.D04.GZ43_(—) AF307053 gi|12018057|gb|AF307053.1AF307053 0 355904Thermococcus litoralis sugar kinase, trehalose/maltose binding protein(malE), trehalose/maltose 22777 2456.H02.GZ43_(—) AJ005821gi|3123571|emb|AJ005821.1HSA5821 5.8E−37 355998 Homo sapiens mRNA forX-like 1 protein 22788 2456.N23.GZ43_(—) AF188746gi|6425045|gb|AF188746.1AF188746 9.6E−63 356163 Homo sapiens prostratekallikrein 2 (KLK2) mRNA, complete cds 22796 2457.C19.GZ43_(—) AF368920gi|14039926|gb|AF368920.1AF368920   1E−47 356279 Caenorhabditis elegansvoltage-dependent calcium channel alpha13 subunit (cca-1) mRNA, completec 22799 2457.D12.GZ43_(—) AK026618 gi|10439509|dbj|AK026618.AK026618 0356296 Homo sapiens cDNA: FLJ22965 fis, clone KAT10418 228102457.H17.GZ43_(—) AE007614 gi|15023883|gb|AE007614.1AE007614   9E−63356397 Clostridium acetobutylicum ATCC824 section 102 of 356 of thecomplete genome 22823 2458.A10.GZ43_(—) AK026920gi|10439892|dbj|AK026920.1AK026920 6.2E−84 356618 Homo sapiens cDNA:FLJ23267 fis, clone COL07266 22827 2458.B23.GZ43_(—) AB050432gi|10998295|dbj|AB050432.1AB050432 4.3E−129 356655 Macaca fascicularisbrain cDNA, clone: QnpA-21861 22829 2458.C06.GZ43_(—) U49973gi|2226003|gb|U49973.1HSU49973   2E−24 356662 Human Tigger1 transposableelement, complete consensus sequence 22842 2458.I09.GZ43_(—) AK023496gi|10435445|dbj|AK023496.1AK023496 2.4E−39 356809 Homo sapiens cDNAFLJ13434 fis, clone PLACE1002578 22843 2458.I10.GZ43_(—) AF031077gi|6649934|gb|AF031077.1AF031077 1.3E−52 356810 Homo sapiens chromosomeX, cosmid LLNLc110C1837, complete sequence 22845 2458.I17.GZ43_(—)AK026569 gi|10439451|dbj|AK026569.1AK026569 1.8E−38 356817 Homo sapienscDNA: FLJ22916 fis, clone KAT06406, highly similar to HSCYCR Human mRNAfor T-cell 22846 2458.I20.GZ43_(—) AF184614gi|6983939|gb|AF184614.1AF184614 4.2E−33 356820 Homo sapiens p47-phox(NCF1) gene, complete cds 22855 2458.N06.GZ43_(—) AF367251gi|14161363|gb|AF367251.1AF367251 2.2E−70 356926 Helicobacter pyloristrain CAPM N93 cytotoxin associated protein A (cagA) gene, complete cds22865 2459.B11.GZ43_(—) AF375597 gi|14150816|gb|AF375597.1AF375596S2 0357027 Mus musculus medium and short chain L-3- hydroxyacyl-Coenzyme Adehydrogenase (Mschad) gene, exo 22866 2459.C05.GZ43_(—) X04803.2gi|6647297|emb|X04803.2HSYUBG1 6.4E−52 357045 Homo sapiens ubiquitingene 22873 2459.F20.GZ43_(—) AK025207 gi|10437672|dbj|AK025207.1AK0252070 357132 Homo sapiens cDNA: FLJ21554 fis, clone COL06330 228772459.H09.GZ43_(—) AB046623 gi|9651056|dbj|AB046623.1AB046623 1.7E−35357169 Macaca fascicularis brain cDNA, clone QccE-10576 228882459.O23.GZ43_(—) AL049301 gi|4500067|emb|AL049301.1HSM800086 1.3E−31357351 Homo sapiens mRNA; cDNA DKFZp564P073 (from clone DKFZp564P073)22889 2459.P24.GZ43_(—) AK018110 gi|12857675|dbj|AK018110.1AK0181101.5E−33 357376 Mus musculus adult male medulla oblongata cDNA, RIKENfull-length enriched library, clone: 633040 22903 2464.H22.GZ43_(—)AB035344 gi|8176599|dbj|AB035344.1AB035344S1 1.1E−127 357870 Homosapiens TCL6 gene, exon 1-10b 22904 2464.I04.GZ43_(—) AK025125gi|10437578|dbj|AK025125.1AK025125 0 357876 Homo sapiens cDNA: FLJ21472fis, clone COL04936 22905 2464.I20.GZ43_(—) AK025966gi|10438647|dbj|AK025966.1AK025966 2.8E−61 357892 Homo sapiens cDNA:FLJ22313 fis, clone HRC05216 22909 2464.K18.GZ43_(—) AF287938gi|12656333|gb|AF287938.1AF287938 8.3E−44 357938 Guichenotia ledifoliaNADH dehydrogenase subunit F (ndhF) gene, partial cds; chloroplast genefor 22912 2464.L15.GZ43_(—) AF141308 gi|5737754|gb|AF141308.1HSPMFG19.9E−76 357959 Homo sapiens polyamine modulated factor-1 (PMF1) gene,exon 1 22918 2464.P17.GZ43_(—) AF052684 gi|2995716|gb|AF052684.1HSPRCAD2  3E−29 358057 Homo sapiens protocadherin 43 gene, exon 2 229342465.J19.GZ43_(—) X02571 gi|31870|emb|X02571.1HSGP5MOS 2.7E−48 358299Human gene fragment related to oncogene c-mos with Alu repeats (locusgp5, region NV-1) 22935 2465.K20.GZ43_(—) AK019509gi|12859761|dbj|AK019509.1AK019509 2.5E−63 358324 Mus musculus 0 dayneonate skin cDNA, RIKEN full-length enriched library, clone:4632435C11, full 22937 2465.L06.GZ43_(—) AK009327gi|12844057|dbj|AK009327.1AK009327 7.9E−73 358334 Mus musculus adultmale tongue cDNA, RIKEN full-length enriched library, clone: 2310012P17,full 22939 2465.M11.GZ43_(—) AK022253 gi|10433611|dbj|AK022253.1AK0222531.4E−112 358363 Homo sapiens cDNA FLJ12191 fis, clone MAMMA1000843 229432466.B02.GZ43_(—) AK023055 gi|10434796|dbj|AK023055.1AK023055 7.5E−39360107 Homo sapiens cDNA FLJ12993 fis, clone NT2RP3000197 229442466.C15.GZ43_(—) AB013897 gi|6177784|dbj|AB013897.1AB013897 4.3E−53360144 Homo sapiens mRNA for HKR1, partial cds 22945 2466.D19.GZ43_(—)AL050141 gi|4884352|emb|AL050141.1HSM800441 3.4E−110 360172 Homo sapiensmRNA; cDNA DKFZp586O031 (from clone DKFZp586O031) 229522466.I08.GZ43_(—) AJ271729 gi|6900103|emb|AJ271729.1HSA271729 6.2E−72360281 Homo sapiens mRNA for glucose-regulated protein (HSPA5 gene)22953 2466.J01.GZ43_(—) AY058527 gi|16197970|gb|AY058527.1 Drosophila9.4E−40 360298 melanogaster LD23445 full length cDNA 229542466.J24.GZ43_(—) AF331425 gi|13375486|gb|AF331425.1AF331425 1.6E−77360321 HIV-1 D311 from Australia envelope protein (env) gene, partialcds 22958 2467.B24.GZ43_(—) AJ005821 gi|3123571|emb|AJ005821.1HSA58211.4E−34 360513 Homo sapiens mRNA for X-like 1 protein 229632467.H18.GZ43_(—) AF036235 gi|2695679|gb|AF036235.1AF036235   2E−169360651 Gorilla gorilla L1 retrotransposon L1Gg- 1A, complete sequence22964 2467.A03.GZ43_(—) BC012960 gi|5277963|gb|BC012960.1BC0129608.7E−36 360468 Mus musculus, ring finger protein 12, clone MGC: 13712IMAGE: 4193003, mRNA, complete cds 22965 2467.A05.GZ43_(—) BC009113gi|14318629|gb|BC009113.1BC009113 4.1E−167 360470 Homo sapiens, cloneMGC: 18122 IMAGE: 4153377, mRNA, complete cds 22969 2467.G01.GZ43_(—)U14573 gi|551542|gb|U14573.1HSU14573   2E−61 360610 ***ALU WARNING:Human Alu-Sq subfamily consensus sequence 22971 2467.N22.GZ43_(—)AF117756 gi|4530440|gb|AF117756.1AF117756 6.8E−77 360799 Homo sapiensthyroid hormone receptor- associated protein complex component TRAP150mRNA, complete 22973 2467.I12.GZ43_(—) AK024049gi|10436318|dbj|AK024049.1AK024049 2.1E−47 360669 Homo sapiens cDNAFLJ13987 fis, clone Y79AA1001963, weakly similar to PUTATIVE PRE-MRNASPLICING 22977 2467.K14.GZ43_(—) AB030001gi|7416074|dbj|AB030001.1AB030001 7.2E−22 360719 Homo sapiens gene forSGRF, complete cds 22979 2467.N03.GZ43_(—) AK023448gi|10435386|dbj|AK023448.1AK023448 0 360780 Homo sapiens cDNA FLJ13386fis, clone PLACE1001104, weakly similar to MYOSIN HEAVY CHAIN, NON-MU22980 2467.N07.GZ43_(—) AK001931 gi|7023502|dbj|AK001931.1AK0019312.3E−54 360784 Homo sapiens cDNA FLJ11069 fis, clone PLACE1004930,highly similar to Homo sapiens MDC-3.13 isofo 22981 2467.N09.GZ43_(—)AE008338 gi|15159908|gb|AE008338.1AE008338 3.7E−50 360786 Agrobacteriumtumefaciens strain C58 linear chromosome, section 142 of 187 of thecomplete sequen 22986 2472.C18.GZ43_(—) K01921gi|339606|gb|K01921.1HUMTGNB   3E−29 360915 Human Asn-tRNA gene, clonepHt6-2, complete sequence and flanks 22992 2472.G03.GZ43_(—) AF321082gi|12958576|gb|AF321082.1AF321082 5.1E−28 360996 HIV-1 isolate DGOB fromFrance envelope glycoprotein (env) gene, complete cds 229992472.M22.GZ43_(—) AF338299 gi|12958808|gb|AF338299.1AF338299 1.4E−145361159 Amazona ochrocephala auropalliata mitochondrial control region 1,partial sequence 23002 2472.P22.GZ43_(—) AJ330257gi|15874675|emb|AJ330257.1HSA330257 1.1E−63 361231 Homo sapiens genomicsequence surrounding NotI site, clone NL1-FA14R 23005 2473.F08.GZ43_(—)AF306355 gi|14573206|gb|AF306355.1AF306355 3.2E−29 361361 Homo sapiensclone TF3.19 immunoglobulin heavy chain variable region mRNA, partialcds 23006 2473.F14.GZ43_(—) AB050477 gi|11034759|dbj|AB050477.1AB0504770 361367 Homo sapiens NIBAN mRNA, complete cds 23011 2473.I08.GZ43_(—)AF224341 gi|15982934|gb|AF224341.1AF224341 8.7E−67 361433 Mus musculusthiamine transporter 1 (S1c19a2) gene, exons 1 through 6 and completecds 23015 2473.O13.GZ43_(—) AF203815 gi|6979641|gb|AF203815.1AF2038155.4E−44 361582 Homo sapiens alpha gene sequence 23018 2474.C08.GZ43_(—)AK000373 gi|7020417|dbj|AK000373.1AK000373 5.6E−47 361673 Homo sapienscDNA FLJ20366 fis, clone HEP18008 23021 2474.G17.GZ43_(—) U75285gi|2315862|gb|U75285.1HSU75285 Homo 1.1E−87 361778 sapiens apoptosisinhibitor survivin gene, complete cds 23023 2474.I06.GZ43_(—) Z81315gi|1644298|emb|Z81315.1HSF62D4 2.1E−67 361815 Human DNA sequence fromfosmid F62D4 on chromosome 22q12-qter 23024 2474.J18.GZ43_(—) AF029062gi|3712662|gb|AF029062.1AF029062 1.2E−28 361851 Homo sapiens DEAD-boxprotein (BAT1) gene, partial cds 23030 2474.P22.GZ43_(—) AL050204gi|4884443|emb|AL050204.1HSM800501 8.9E−33 361999 Homo sapiens mRNA;cDNA DKFZp586F1223 (from clone DKFZp586F1223) 23031 2475.A05.GZ43_(—)AL109666 gi|5689800|emb|AL109666.1IRO35907 6.3E−43 362006 Homo sapiensmRNA full length insert cDNA clone EUROIMAGE 35907 230322475.C18.GZ43_(—) AK023739 gi|10435762|dbj|AK023739.1AK023739 2.8E−180362067 Homo sapiens cDNA FLJ13677 fis, clone PLACE1011982 230332475.E18.GZ43_(—) AK024206 gi|10436527|dbj|AK024206.1AK024206 1.9E−21362115 Homo sapiens cDNA FLJ14144 fis, clone MAMMA1002909 230352475.H06.GZ43_(—) AF322634 gi|12657820|gb|AF322634.1AF322634S1 1.2E−173362175 Human herpesvirus 3 strain VZV-Iceland glycoprotein B gene,complete cds 23036 2475.H13.GZ43_(—) AF026853gi|3882436|gb|AF026853.1HSHADHSC 1 2.1E−30 362182 Homo sapiensmitochondrial short-chain L- 3-hydroxyacyl-CoA dehydrogenase (HADHSC)gene, nuclear 23039 2475.N08.GZ43_(—) AK011295gi|12847322|dbj|AK011295.1AK011295 1.1E−84 362321 Mus musculus 10 daysembryo cDNA, RIKEN full-length enriched library, clone: 2610002L04, fullins 23045 2475.M20.GZ43_(—) AK023843 gi|10435902|dbj|AK023843.1AK0238438.8E−42 362309 Homo sapiens cDNA FLJ13781 fis, clone PLACE4000465 230462475.N21.GZ43_(—) S45332 gi|255496|gb|S45332.1S45332 1.4E−101 362334erythropoietin receptor [human, placental, Genomic, 8647 nt] 230552480.G11.GZ43_(—) X83497 gi|603558|emb|X83497.1HSLTRERV9 6.1E−40 358658H. sapiens DNA for ZNF80-linked ERV9 long terminal repeat 230562480.H06.GZ43_(—) AB002070 gi|12862447|dbj|AB002070.1AB002070 5.5E−28358677 Aspergillus clavatus gene for 18S rRNA, partial sequence, strain:NRRL 1 23061 2480.M20.GZ43_(—) AL1576971gi|11121002|emb|AL157697.11AL157697 9.3E−36 358811 Human DNA sequencefrom clone RP5- 1092C14 on chromosome 6, complete sequence [Homosapiens] 23064 2480.P23.GZ43_(—) AB037719gi|7242950|dbj|AB037719.1AB037719 3.6E−35 358886 Homo sapiens mRNA forKIAA1298 protein, partial cds 23065 2481.B06.GZ43_(—) AK023471gi|10435415|dbj|AK023471.1AK023471 0 358917 Homo sapiens cDNA FLJ13409fis, clone PLACE1001716 23068 2481.D10.GZ43_(—) AL021306gi|2808416|emb|AL021306.1HS1109B5   7E−52 358969 Human DNA sequence fromclone CTB- 1109B5 on chromosome 22 Contains a GSS, complete sequence[Homo 23069 2481.D13.GZ43_(—) X64467 gi|28579|emb|X64467.1HSALADG4.2E−53 358972 H. sapiens ALAD gene for porphobilinogen synthase 230752481.K12.GZ43_(—) AK026901 gi|10439868|dbj|AK026901.1AK026901 5.9E−52359139 Homo sapiens cDNA: FLJ23248 fis, clone COL03555 230832482.E17.GZ43_(—) AK022821 gi|10434440|dbj|AK022821.1AK022821 9.4E−35359384 Homo sapiens cDNA FLJ12759 fis, clone NT2RP2001347 230842482.E20.GZ43_(—) AK014328 gi|12852104|dbj|AK014328.1AK014328 5.2E−99359387 Mus musculus 14, 17 days embryo head cDNA, RIKEN full-lengthenriched library, clone: 3230401M21, 23091 2482.N09.GZ43_(—) AE008514gi|15459095|gb|AE008514.1AE008514 6.9E−107 359592 Streptococcuspneumoniae R6 section 130 of 184 of the complete genome 231002483.J07.GZ43_(—) AK022722 gi|10434285|dbj|AK022722.1AK022722   1E−300359878 Homo sapiens cDNA FLJ12660 fis, clone NT2RM4002174, moderatelysimilar to MRP PROTEIN 23101 2483.K02.GZ43_(—) AK012908gi|12849956|dbj|AK012908.1AK012908 3.7E−189 359897 Mus musculus 10, 11days embryo cDNA, RIKEN full-length enriched library, clone: 2810046L04,full 23106 2483.O07.GZ43_(—) AK014328 gi|12852104|dbj|AK014328.1AK0143283.2E−103 359998 Mus musculus 14, 17 days embryo head cDNA, RIKENfull-length enriched library, clone: 3230401M21, 23108 2488.C19.GZ43_(—)AB023199 gi|4589607|dbj|AB023199.1AB023199 1.1E−50 362511 Homo sapiensmRNA for KIAA0982 protein, complete cds 23110 2488.E20.GZ43_(—) AK001136gi|7022203|dbj|AK001136.1AK001136   1E−35 362560 Homo sapiens cDNAFLJ10274 fis, clone HEMBB1001169 23111 2488.F06.GZ43_(—) AK011295gi|12847322|dbj|AK011295.1AK011295 8.1E−55 362570 Mus musculus 10 daysembryo cDNA, RIKEN full-length enriched library, clone: 2610002L04, fullins 23113 2488.G02.GZ43_(—) X15723 gi|31481|emb|X15723.1HSFURIN Human1.8E−85 362590 fur gene, exons 1 through 8 23117 2488.K04.GZ43_(—)AF026853 gi|3882436|gb|AF026853.1HSHADHSC 1 2.1E−30 362688 Homo sapiensmitochondrial short-chain L- 3-hydroxyacyl-CoA dehydrogenase (HADHSC)gene, nuclear 23122 2489.A03.GZ43_(—) AB050477gi|11034759|dbj|AB050477.1AB050477 6.7E−46 362831 Homo sapiens NIBANmRNA, complete cds 23124 2489.A13.GZ43_(—) AK026618gi|10439509|dbj|AK026618.1AK026618 1.8E−178 362841 Homo sapiens cDNA:FLJ22965 fis, clone KAT10418 23127 2489.D18.GZ43_(—) AF086310gi|3483655|gb|AF086310.1HUMZD51F08 2.5E−79 362918 Homo sapiens fulllength insert cDNA clone ZD51F08 23128 2489.F09.GZ43_(—) AF271388gi|8515842|gb|AF271388.1AF271388 0 362957 Homo sapiensCMP-N-acetylneuraminic acid synthase mRNA, complete cds 231292489.G05.GZ43_(—) AK023739 gi|10435762|dbj|AK023739.1AK023739 6.8E−209362977 Homo sapiens cDNA FLJ13677 fis, clone PLACE1011982 231402489.M11.GZ43_(—) AE008029 gi|15155994|gb|AE008029.1AE008029 4.2E−44363127 Agrobacterium tumefaciens strain C58 circular chromosome, section87 of 254 of the complete seque 23144 2490.B06.GZ43_(—) AK001915gi|7023475|dbj|AK001915.1AK001915 1.7E−43 363242 Homo sapiens cDNAFLJ11053 fis, clone PLACE1004664 23155 2490.J22.GZ43_(—) AF026853gi|3882436|gb|AF026853.1HSHADHSC 1   2E−30 363450 Homo sapiensmitochondrial short-chain L- 3-hydroxyacyl-CoA dehydrogenase (HADHSC)gene, nuclear 23160 2490.N24.GZ43_(—) AF167438gi|9622123|gb|AF167438.1AF167438 8.8E−74 363548 Homo sapiensandrogen-regulated short- chain dehydrogenase/reductase 1 (ARSDR1) mRNA,complete cds 23163 2491.C13.GZ43_(—) AK022338gi|10433714|dbj|AK022338.1AK022338 6.2E−30 363657 Homo sapiens cDNAFLJ12276 fis, clone MAMMA1001692 23174 2491.P10.GZ43_(—) AJ276936gi|12214232|emb|AJ276936.1NME276936 0 363966 Neisseria meningitidispartial tbpB gene for transferrin binding protein B subunit, allele 66,23175 2491.P20.GZ43_(—) AY027632 gi|15418751|gb|AY027632.1 Measles7.8E−283 363976 virus strain MVs/Masan.KOR/49.00/2 hemagglutinin (H)mRNA, complete cds 23177 2496.C08.GZ43_(—) U67829gi|2289943|gb|U67829.1HSU67829 3.6E−90 364139 Human primary Alutranscript 23181 2496.F14.GZ43_(—) X16983 gi|33945|emb|X16983.1HSINTAL44.7E−53 364217 Human mRNA for integrin alpha-4 subunit 231832496.I06.GZ43_(—) BC004138 gi|13278716|gb|BC004138.1BC004138 8.3E−53364281 Homo sapiens, ribosomal protein L6, clone MGC: 1635 IMAGE:2823733, mRNA, complete cds 23184 2496.K15.GZ43_(—) NM_024711gi|13376008|ref|NM_024711.1 Homo 1.1E−28 364338 sapiens hypotheticalprotein FLJ22690 (FLJ22690), mRNA 23192 2497.E09.GZ43_(—) AF284421gi|15088516|gb|AF284421.1AF284421 4.1E−158 364572 Homo sapienscomplement factor MASP-3 mRNA, complete cds 23195 2497.J05.GZ43_(—)Z56298 gi|1027529|emb|Z56298.1HS10C4R 2.5E−42 364688 H. sapiens CpGisland DNA genomic Mse1 fragment, clone 10c4, reverse read cpg10c4.rt1a23199 2497.L05.GZ43_(—) AK023448 gi|10435386|dbj|AK023448.1AK023448 0364736 Homo sapiens cDNA FLJ13386 fis, clone PLACE1001104, weaklysimilar to MYOSIN HEAVY CHAIN, NON-MU 23207 2562.B09.GZ43_(—) M64241gi|190813|gb|M64241.1HUMQM Human 3.2E−52 375496 Wilm's tumor-relatedprotein (QM) mRNA, complete cds 23210 2562.I01.GZ43_(—) AF083247gi|5106788|gb|AF083247.1AF083247 2.4E−48 375656 Homo sapiens MDG1 mRNA,complete cds 23214 2562.O01.GZ43_(—) AF223389gi|11066459|gb|AF223389.1AF223389 8.7E−57 375800 Homo sapiens PCGEM1gene, non-coding mRNA 23217 2562.H11.GZ43_(—) AK023442gi|10435378|dbj|AK023442.1AK023442 1.7E−64 375642 Homo sapiens cDNAFLJ13380 fis, clone PLACE1001007 23218 2562.B24.GZ43_(—) AF287932gi|12656321|gb|AF287932.1AF287932 1.8E−31 375511 Rayleya bahiensis NADHdehydrogenase subunit F (ndhF) gene, partial cds; chloroplast gene forchl 23229 2498.A02.GZ43_(—) AY031766 gi|13738569|gb|AY031766.1 HIV-1isolate 1.3E−29 364853 NC5203-1999 from USA pol polyprotein (pol) gene,partial cds 23230 2498.A19.GZ43_(—) AL122114gi|6102936|emb|AL122114.1HSM801274   1E−59 364870 Homo sapiens mRNA;cDNA DKFZp434K0221 (from clone DKFZp434K0221); partial cds 232352498.G15.GZ43_(—) M86752 gi|184564|gb|M86752.1HUMIEF Human 3.4E−54365010 transformation-sensitive protein (IEF SSP 3521) mRNA, completecds 23238 2498.I17.GZ43_(—) AJ335654 gi|15880072|emb|AJ335654.1HSA3356544.3E−41 365060 Homo sapiens genomic sequence surrounding NotI site,clone NR5-IJ21R 23239 2498.K20.GZ43_(—) X15940gi|36129|emb|X15940.1HSRPL31 Human 1.7E−25 365111 mRNA for ribosomalprotein L31 23240 2498.M19.GZ43_(—) AF203815gi|6979641|gb|AF203815.1AF203815   4E−47 365158 Homo sapiens alpha genesequence 23242 2498.P07.GZ43_(—) AF410975gi|15553753|gb|AF410975.1AF410975 3.5E−29 365218 Measles virus genotypeD4 strain MVi/Montreal.CAN/12.89 hemagglutinin gene, complete cds 232442507.C03.GZ43_(—) NM_025080 gi|13376633|ref|NM_025080.1 Homo   1E−232366992 sapiens hypothetical protein FLJ22316 (FLJ22316), mRNA 232592511.J18.GZ43_(—) M81806 gi|184406|gb|M81806.1HUMHSKPQZ7 4.7E−34 369643Human housekeeping (Q1Z 7F5) gene, exons 2 through 7, complete cds 232612499.A22.GZ43_(—) AK024860 gi|10437268|dbj|AK024860.1AK024860 6.4E−49365257 Homo sapiens cDNA: FLJ21207 fis, clone COL00362 232632499.C09.GZ43_(—) AJ330464 gi|15874882|emb|AJ330464.1HSA330464 3.3E−100365292 Homo sapiens genomic sequence surrounding NotI site, cloneNR1-IL7C 23268 Clu1009284.1 AF026853 gi|3882436|gb|AF026853.1HSHADHSC 11.3E−30 Homo sapiens mitochondrial short-chain L- 3-hydroxyacyl-CoAdehydrogenase (HADHSC) gene, nuclear 23269 Clu1022935.2 AL590711.7gi|16304966|emb|AL590711.7AL590711 3.9E−118 Human DNA sequence fromclone RP11- 284O18 on chromosome 9, complete sequence [Homo sapiens]23270 Clu1037152.1 M87652 gi|182743|gb|M87652.1HUMFPRPR 1.1E−21 Humanformylpeptide receptor gene, promoter region 23271 Clu13903.1 AK026618gi|10439509|dbj|AK026618.1AK026618 1.5E−293 Homo sapiens cDNA: FLJ22965fis, clone KAT10418 23272 Clu139979.2 AB056828gi|13365953|dbj|AB056828.1AB056828 1.4E−33 Macaca fascicularis braincDNA clone: QflA-13447, full insert sequence 23274 Clu187860.2 AL050204gi|4884443|emb|AL050204.1HSM800501 4.7E−33 Homo sapiens mRNA; cDNADKFZp586F1223 (from clone DKFZp586F1223) 23275 Clu189993.1 AB030001gi|7416074|dbj|AB030001.1AB030001 9.6E−87 Homo sapiens gene for SGRF,complete cds 23276 Clu20975.1 AF039687 gi|3170173|gb|AF039687.1AF0396872.7E−190 Homo sapiens antigen NY-CO-1 (NY-CO-) 1) mRNA, complete cds23278 Clu218833.1 AF223389 gi|11066459|gb|AF223389.1AF223389   1E−139Homo sapiens PCGEM1 gene, non-coding mRNA 23279 Clu244504.2 Z59663gi|1031576|emb|Z59663.1HS168F9F 7.5E−22 H. sapiens CpG island DNAgenomic Mse1 fragment, clone 168f9, forward read cpg168f9.ft1a 23281Clu376516.1 AK018003 gi|12857525|dbj|AK018003.1AK018003 1.7E−63 Musmusculus adult male thymus cDNA, RIKEN full-length enriched library,clone: 5830450H20, full 23282 Clu376630.1 U93571gi|2072968|gb|U93571.1HSU93571 8.7E−291 Human L1 element L1.24 p40 gene,complete cds 23283 Clu377044.2 AK024860gi|10437268|dbj|AK024860.1AK024860 1.6E−49 Homo sapiens cDNA: FLJ21207fis, clone COL00362 23284 Clu379689.1 BC007110gi|13937991|gb|BC007110.1BC007110 0 Homo sapiens, clone MGC: 14768IMAGE: 4291902, mRNA, complete cds 23286 Clu387530.4 AK009770gi|12844769|dbj|AK009770.1AK009770 1.5E−80 Mus musculus adult maletongue cDNA, RIKEN full-length enriched library, clone: 2310043C14, full23287 Clu388450.2 AK023448 gi|10435386|dbj|AK023448.1AK023448 0 Homosapiens cDNA FLJ13386 fis, clone PLACE1001104, weakly similar to MYOSINHEAVY CHAIN, NON-MU 23288 Clu396325.1 Z78727gi|1508005|emb|Z78727.1HSPA15B9 1.2E−38 H. sapiens flow-sortedchromosome 6 HindIII fragment, SC6pA15B9 23291 Clu400258.1 AB038971gi|12862672|dbj|AB038971.1AB038965S7   4E−74 Homo sapiens CFLAR gene,exon 10, exon 11 23293 Clu402591.3 AF170811gi|6715105|gb|AF170811.AF170811   7E−26 Homo sapiens CaBP2 (CABP2) gene,complete cds 23295 Clu404081.2 AK011443gi|12847570|dbj|AK011443.1AK011443   5E−153 Mus musculus 10 days embryocDNA, RIKEN full-length enriched library, clone: 2610018B07, full ins23297 Clu41346.1 AB042029 gi|16326128|dbj|AB042029.1AB042029 0 Homosapiens DEPC-1 mRNA for prostate cancer antigen-1, complete cds 23299Clu416124.1 AK000293 gi|7020278|dbj|AK000293.1AK000293 3.3E−34 Homosapiens cDNA FLJ20286 fis, clone HEP04358 23300 Clu417672.1 AK027667gi|14042514|dbj|AK027667.1AK027667 1.6E−183 Homo sapiens cDNA FLJ14761fis, clone NT2RP3003302 23301 Clu423664.1 AF287270gi|9844925|gb|AF287270.1AF287270 6.3E−34 Homo sapiens mucolipin (MCOLN1)gene, complete cds 23303 Clu442923.3 BC014256gi|15559816|gb|BC014256.1BC014256 1.5E−236 Homo sapiens, Similar toguanine nucleotide binding protein (G protein), beta polypeptide 2-like23304 Clu446975.1 AL022342.6 gi|7159715|emb|AL022342.6HS29M10 1.8E−74Human DNA sequence from clone RP1- 29M10 on chromosome 20, completesequence [Homo sapiens] 23305 Clu449839.2 BC001607gi|12804410|gb|BC001607.1BC001607 1.9E−27 Homo sapiens, clone IMAGE:3543874, mRNA, partial cds 23306 Clu449889.1 S45332gi|255496|gb|S45332.1S45332   8E−101 erythropoietin receptor [human,placental, Genomic, 8647 nt] 23307 Clu451707.2 AJ004862gi|4038586|emb|AJ004862.1HSAJ4862 4.7E−49 Homo sapiens partial MUC5Bgene, exon 1-29 23308 Clu454509.3 AK022973gi|10434673|dbj|AK022973.1AK022973 1.7E−285 Homo sapiens cDNA FLJ12911fis, clone NT2RP2004425, highly similar to Mus musculus axotrophin mR23310 Clu455862.1 AK023951 gi|10436049|dbj|AK023951.1AK023951 3.3E−27Homo sapiens cDNA FLJ13889 fis, clone THYRO1001595 23311 Clu460493.1AK012865 gi|12849888|dbj|AK012865.1AK012865 1.7E−57 Mus musculus 10, 11days embryo cDNA, RIKEN full-length enriched library, clone: 2810036K01,full 23314 Clu470032.1 AF223389 gi|11066459|gb|AF223389.1AF2233891.2E−116 Homo sapiens PCGEM1 gene, non-coding mRNA 23317 Clu477271.1BC007307 gi|13938350|gb|BC007307.1BC007307 4.6E−56 Homo sapiens, Similarto zinc finger protein 268, clone IMAGE: 3352268, mRNA, partial cds23318 Clu480410.1 AK000713 gi|7020973|dbj|AK000713.1AK000713 0 Homosapiens cDNA FLJ20706 fis, clone KAIA1273 23320 Clu497138.1 AF270579gi|9755121|gb|AF270579.1AF270579 3.8E−29 Homo sapiens clone 18ptel_481c6sequence 23321 Clu498886.1 U49973 gi|2226003|gb|U49973.1HSU49973 1.4E−24Human Tigger1 transposable element, complete consensus sequence 23323Clu5013.2 BC007458 gi|13938610|gb|BC007458.1BC007458 0 Homo sapiens,clone MGC: 12217 IMAGE: 3828631, mRNA, complete cds 23324 Clu5105.2AL512712 gi|12224956|emb|AL512712.1HSM80291 0 5 Homo sapiens mRNA; cDNADKFZp761J139 (from clone DKFZp761J139) 23325 Clu510539.2 AK023812gi|10435860|dbj|AK023812.1AK023812 1.4E−32 Homo sapiens cDNA FLJ13750fis, clone PLACE3000331 23326 Clu514044.1 AJ403947gi|14270388|emb|AJ403947.1HSA403947 4.4E−295 Homo sapiens partialSLC22A3 gene for organic cation transporter 3, exon 2 23329 Clu520370.1AF093016 gi|5579305|gb|AF093016.1AF093016 7.3E−67 Homo sapiens 22k48gene, 5′UTR 23330 Clu524917.1 AL1573620gi|15028613|emb|AL157362.10AL157362 4.9E−23 Human DNA sequence fromclone RP11- 142D16 on chromosome 13q14.3-21.31, complete sequence [Homo23331 Clu528957.1 AB060919 gi|13874604|dbj|AB060919.1AB060919 1.5E−31Macaca fascicularis brain cDNA clone: QtrA-14728, full insert sequence23334 Clu540142.2 AJ005821 gi|3123571|emb|AJ005821.1HSA5821 3.5E−36 Homosapiens mRNA for X-like 1 protein 23335 Clu540379.2 AF088011gi|3523217|gb|AF088011.1HUMYY75G10 2.4E−49 Homo sapiens full lengthinsert cDNA clone YY75G10 23336 Clu549507.1 U14571gi|551540|gb|U14571.1HSU14571 1.6E−48 ***ALU WARNING: Human Alu-Scsubfamily consensus sequence 23339 Clu556827.3 AB038163gi|10280537|dbj|AB038163.1AB038163 9.7E−22 Homo sapiens NDUFV3 gene formitochondrial NADH-Ubiquinone oxidoreductase, complete cds 23340Clu558569.2 AF061258 gi|3108092|gb|AF061258.1AF061258   1E−300 Homosapiens LIM protein mRNA, complete cds 23343 Clu570804.1 AK023843gi|10435902|dbj|AK023843.1AK023843 4.4E−42 Homo sapiens cDNA FLJ13781fis, clone PLACE4000465 23344 Clu572170.2 U18271gi|885681|gb|U18271.1HSTMPO6 Human 4.9E−57 thymopoietin (TMPO) gene,partial exon 6, complete exon 7, partial exon 8, and partial cds for t23346 Clu587168.1 AJ276804 gi|10803412|emb|AJ276804.1HSA276804 5.8E−69Homo sapiens mRNA for protocadherin (PCDHX gene) 23347 Clu588996.1U73166 gi|1613889|gb|U73166.1U73166 Homo 9.3E−22 sapiens cosmid cloneLUCA15 from 3p21.3, complete sequence 23349 Clu598388.1 AF327178gi|11878341|gb|AF327178.1AF327178 1.1E−26 Homo sapiens clone20ptel_cA35_21t7 sequence 23350 Clu604822.2 AB063021gi|14388457|dbj|AB063021.1AB063021 2.6E−65 Macaca fascicularis braincDNA clone: QmoA-11389, full insert sequence 23353 Clu627263.1 AK021759gi|10433005|dbj|AK021759.1AK021759 5.7E−30 Homo sapiens cDNA FLJ11697fis, clone HEMBA1005035 23356 Clu641662.2 AL1576971gi|11121002|emb|AL157697.11AL157697   7E−84 Human DNA sequence fromclone RP5- 1092C14 on chromosome 6, complete sequence [Homo sapiens]23358 Clu6712.1 AK024029 gi|10436287|dbj|AK024029.1AK024029 0 Homosapiens cDNA FLJ13967 fis, clone Y79AA1001402, weakly similar to Homosapiens paraneoplasti 23361 Clu685244.2 S56773gi|298606|gb|S56773.1S56773 putative 1.1E−35 serine-threonine proteinkinase {3′ UTR, Alu repeats} [human, Genomic, 1470 nt] 23362 Clu691653.1D28126 gi|559316|dbj|D28126.1HUMATPSAS 6.3E−37 Human gene for ATPsynthase alpha subunit, complete cds (exon 1 to 12) 23367 Clu709796.2AB070013 gi|15207866|dbj|AB070013.1AB070013 8.4E−118 Macaca fascicularistestis cDNA clone: QtsA-11243, full insert sequence 23369 Clu727966.1AF271388 gi|8515842|gb|AF271388.1AF271388 0 Homo sapiensCMP-N-acetylneuraminic acid synthase mRNA, complete cds 23372Clu756337.1 BC004923 gi|13436241|gb|BC004923.1BC004923 4.1E−250 Homosapiens, clone IMAGE: 3605104, mRNA, partial cds 23376 Clu823296.3AK023179 gi|10434987|dbj|AK023179.1AK023179 6.4E−33 Homo sapiens cDNAFLJ13117 fis, clone NT2RP3002660 23377 Clu830453.2 AK027301gi|14041890|dbj|AK027301.1AK027301 0 Homo sapiens cDNA FLJ14395 fis,clone HEMBA1003250, weakly similar to PROTEIN KINASE APK1A (EC 2 23378Clu839006.1 AB023199 gi|4589607|dbj|AB023199.1AB023199 3.3E−51 Homosapiens mRNA for KIAA0982 protein, complete cds 23379 Clu847088.1AL078632.6 gi|6002309|emb|AL078632.6HSA255N20 4.2E−40 Human DNA sequencefrom clone 255N20 on chromosome 22, complete sequence [Homo sapiens]23380 Clu853371.2 S79349 gi|1110571|gb|S79349.1S79349 Homo 1.6E−48sapiens type 1 iodothyronine deiodinase (hdiol) gene, partial cds 23381Clu88462.1 AF026855 gi|3882438|gb|AF026855.1HSHADHSC 3 1.1E−65 Homosapiens mitochondrial short-chain L- 3-hydroxyacyl-CoA dehydrogenase(HADHSC) gene, nuclear 23382 Clu935908.2 AK025271gi|10437753|dbj|AK025271.1AK025271 8.2E−54 Homo sapiens cDNA: FLJ21618fis, clone COL07487 23386 DTT00087024.1 AF036235gi|2695679|gb|AF036235.1AF036235 0 Gorilla gorilla L1 retrotransposonL1Gg- 1A, complete sequence 23387 DTT00089020.1 AF324172gi|12958747|gb|AF324172.1AF324172 1.1E−142 Dictyophora indusiata strainASI 32001 internal transcribed spacer 1, partial sequence; 5.8S ribo23388 DTT00171014.1 AB050477 gi|11034759|dbj|AB050477.1AB050477 0 Homosapiens NIBAN mRNA, complete cds 23389 DTT00514029.1 BC001978gi|12805042|gb|BC001978.1BC001978   6E−284 Homo sapiens, clone IMAGE:3461487, mRNA, partial cds 23390 DTT00740010.1 AF216292gi|7229461|gb|AF216292.1AF216292 9.5E−229 Homo sapiens endoplasmicreticulum lumenal Ca2+ binding protein grp78 mRNA, complete cds 23391DTT00945030.1 AL117237 gi|5834563|emb|AL117237.1HS328E191 0 Novel humangene mapping to chomosome 1 23394 DTT01315010.1 X16983gi|33945|emb|X16983.1HSINTAL4 0 Human mRNA for integrin alpha-4 subunit23395 DTT01503016.1 AK025473 gi|10437996|dbj|AK025473.1AK025473 0 Homosapiens cDNA: FLJ21820 fis, clone HEP01232 23396 DTT01555018.1 AE007613gi|15023874|gb|AE007613.1AE007613 0 Clostridium acetobutylicum ATCC824section 101 of 356 of the complete genome 23397 DTT01685047.1 M54985gi|177005|gb|M54985.1GIBBGLOETAH. 6.8E−107 lar psi-eta beta-like globinpseudogene, exon 1, 2, 3 23398 DTT01764019.1 AF307053gi|12018057|gb|AF307053.1AF307053 0 Thermococcus litoralis sugar kinase,trehalose/maltose binding protein (malE), trehalose/maltose 23401DTT02367007.1 AK001580 gi|7022920|dbj|AK001580.1AK001580 0 Homo sapienscDNA FLJ10718 fis, clone NT2RP3001096, weakly similar to Rattusnorvegicus leprecan 23402 DTT02671007.1 AF384048gi|14488027|gb|AF384048.1AF384048 1.8E−170 Homo sapiens interferon kappaprecursor gene, complete cds 23403 DTT02737017.1 AF182418gi|10197635|gb|AF182418.1AF182418   9E−207 Homo sapiens MDS017 (MDS017)mRNA, complete cds 23404 DTT02850005.1 AK011295gi|12847322|dbj|AK011295.1AK011295 2.5E−141 Mus musculus 10 days embryocDNA, RIKEN full-length enriched library, clone: 2610002L04, full ins23406 DTT03037029.1 AE006916 gi|13879055|gb|AE006916.1AE006916 2.1E−129Mycobacterium tuberculosis CDC1551, section 2 of 280 of the completegenome 23407 DTT03150008.1 M83822 gi|1580780|gb|M83822.1HUMCDC4REL 0Human beige-like protein (BGL) mRNA, partial cds 23408 DTT03367008.1NM_012090.2 gi|15011903|ref|NM_012090.2 Homo 0 sapiens actincross-linking factor (ACF7), transcript variant 1, mRNA 23411DTT03913023.1 AK018110 gi|12857675|dbj|AK018110.1AK018110   2E−214 Musmusculus adult male medulla oblongata cDNA, RIKEN full-length enrichedlibrary, clone: 633040 23412 DTT03978010.1 BC015529gi|15930193|gb|BC015529.1BC015529 0 Homo sapiens, Similar to ribose 5-phosphate isomerase A, clone MGC: 9441 IMAGE: 3904718, mRNA, comp 23413DTT04070014.1 L43411 gi|893273|gb|L43411.1HUM25DC1Z   4E−102 Homosapiens (subclone 5_g5 from P1 H25) DNA sequence 23414 DTT04084010.1AF259790 gi|12240019|gb|AF259790.1AF259790 2.2E−288 Desulfitobacteriumsp. PCE-1 o- chlorophenol reductive dehalogenase (cprA) gene, completecds 23415 DTT04160007.1 AF338299 gi|12958808|gb|AF338299.1AF3382991.4E−181 Amazona ochrocephala auropalliata mitochondrial control region1, partial sequence 23417 DTT04378009.1 AF102129gi|5922722|gb|AF102129.1AF102129 4.7E−146 Rattus norvegicus KPL2 (Kpl2)mRNA, complete cds 23418 DTT04403013.1 AE007580gi|15023517|gb|AE007580.1AE007580 1.5E−199 Clostridium acetobutylicumATCC824 section 68 of 356 of the complete genome 23420 DTT04660017.1NM_025079 gi|13376631|ref|NM_025079.1 Homo 0 sapiens hypotheticalprotein FLJ23231 (FLJ23231), mRNA 23421 DTT04956054.1 AF050179gi|3319283|gb|AF050179.1AF050179 0 Homo sapiens CENP-C binding protein(DAXX) mRNA, complete cds 23422 DTT04970018.1 AK015635gi|12854041|dbj|AK015635.1AK015635 1.4E−84 Mus musculus adult maletestis cDNA, RIKEN full-length enriched library, clone: 4930486L24, full23424 DTT05571010.1 AB014533 gi|3327079|dbj|AB014533.1AB014533 1.8E−53Homo sapiens mRNA for KIAA0633 protein, partial cds 23426 DTT05742029.1AF344987 gi|13448249|gb|AF344987.1AF344987 0 Hepatitis C virus isolateRDpostSC1c2 polyprotein gene, partial cds 23427 DTT06137030.1 AY049285gi|15146287|gb|AY049285.1 Arabidopsis 2.2E−143 thalianaAT3g58570/F14P22_160 mRNA, complete cds 23428 DTT06161014.1 AJ330465gi|15874883|emb|AJ330465.1HSA330465 2.5E−28 Homo sapiens genomicsequence surrounding NotI site, clone NR1-IM15C 23429 DTT06706019.1AF226787 gi|12407487|gb|AF226787.1AF226787 0 Syrrhopodon confertusribulose-1,5- bisphosphate carboxylase large subunit (rbcL) gene,partial cd 23430 DTT06837021.1 AK000658 g|7020892|dbj|AK000658.1AK0006580 Homo sapiens cDNA FLJ20651 fis, clone KAT01814 23431 DTT07040015.1AF047347 gi|3005557|gb|AF047347.1AF047347 0 Homo sapiens adaptor proteinX11alpha mRNA, complete cds 23432 DTT07088009.1 AF326517gi|15080738|gb|AF326517.1AF326517 0 Abies grandis pinene synthase gene,partial cds 23433 DTT07182014.1 AB035187gi|9955412|dbj|AB035187.1AB035187 3.1E−84 Homo sapiens RHD gene, intron1, complete sequence 23434 DTT07405044.1 AP002946gi|16267254|dbj|AP002946.1AP002946 0 Mastacembelus favus mitochondrialDNA, complete genome 23435 DTT07408020.1 AE008061gi|15156405|gb|AE008061.1AE008061 6.9E−245 Agrobacterium tumefaciensstrain C58 circular chromosome, section 119 of 254 of the complete sequ23438 DTT08005024.1 U18270 gi|885679|gb|U18270.1HSTMPO4 Human 5.1E−108thymopoietin (TMPO) gene, exons 4 and 5, and complete cds forthymopoietin alpha 23439 DTT08098020.1 AF387946gi|15021617|gb|AF387946.1AF387946 0 Homo sapiens clone J102 melanocortin1 receptor gene, promoter region 23440 DTT08167018.1 NM_020642gi|11034852|ref|NM_020642.1 Homo   1E−183 sapiens chromosome 11 openreading frame 17 (C11orf17), mRNA 23441 DTT08249022.1 M86752gi|184564|gb|M86752.1HUMIEF Human 0 transformation-sensitive protein(IEF SSP 3521) mRNA, complete cds 23443 DTT08514022.1 AK001927gi|7023494|dbj|AK001927.1AK001927 0 Homo sapiens cDNA FLJ11065 fis,clone PLACE1004868, weakly similar to MALE STERILITY PROTEIN 2 23444DTT08527013.1 AF271388 gi|8515842|gb|AF271388.1AF271388 0 Homo sapiensCMP-N-acetylneuraminic acid synthase mRNA, complete cds 23445DTT08595020.1 L07758 gi|177764|gb|L07758.1HUM56KDAPR 0 Human IEF SSP9502 mRNA, complete cds 23446 DTT08711019.1 D87930gi|2443337|dbj|D87930.1D87930 Homo 0 sapiens mRNA for myosin phosphatasetarget subunit 1 (MYPT1) 23447 DTT08773020.1 X15187gi|37260|emb|X15187.1HSTRA1 Human 6.8E−298 tral mRNA for human homologueof murine tumor rejection antigen gp96 23448 DTT08874012.1 AK026442gi|10439307|dbj|AK026442.1AK026442 0 Homo sapiens cDNA: FLJ22789 fis,clone KAIA2171 23449 DTT09387018.1 AF273672gi|15186755|gb|AF273672.1AF273672 0 Mus musculus RANBP9 isoform 1(Ranbp9) mRNA, complete cds 23450 DTT09396022.1 AK000913gi|7021874|dbj|AK000913.1AK000913 0 Homo sapiens cDNA FLJ10051 fis,clone HEMBA1001281 23452 DTT09604016.1 AK022722gi|10434285|dbj|AK022722.1AK022722 2.2E−198 Homo sapiens cDNA FLJ12660fis, clone NT2RM4002174, moderately similar to MRP PROTEIN 23454DTT09742009.1 AF025409 gi|2582414|gb|AF025409.1AF025409 0 Homo sapienszinc transporter 4 (ZNT4) mRNA, complete cds 23455 DTT09753017.1 L03532gi|187280|gb|L03532.1HUMM4PRO 5.7E−58 Human M4 protein mRNA, completecds 23456 DTT09793019.1 AK025125 gi|10437578|dbj|AK025125.1AK025125 Homosapiens cDNA: FLJ21472 fis, clone COL04936 23457 DTT09796028.1 AF272390gi|8705239|gb|AF272390.1AF272390 0 Homo sapiens myosin 5c (MYO5C) mRNA,complete cds 23459 DTT10360040.1 AJ133798gi|6453351|emb|AJ133798.1HSA133798 0 Homo sapiens mRNA for copine VIprotein 23460 DTT10539016.1 AF152924 gi|5453323|gb|AF152924.1AF152924Mus 2.6E−70 musculus syntaxin4-interacting protein synip mRNA, completecds 23461 DTT10564022.1 AF322634 gi|12657820|gb|AF322634.1AF322634S1 0Human herpesvirus 3 strain VZV-Iceland glycoprotein B gene, complete cds23462 DTT10683041.1 X69392 gi|36114|emb|X69392.1HSRP26AA   3E−250 H.sapiens mRNA for ribosomal protein L26 23463 DTT10819011.1 U14568gi|551537|gb|U14568.1HSU14568 2.6E−93 ***ALU WARNING: Human Alu-Sbsubfamily consensus sequence 23465 DTT11479018.1 AF309561gi|10954043|gb|AF309561.1AF309561 0 Homo sapiens KRAB zinc fingerprotein ZFQR mRNA, complete cds 23466 DTT11483012.1 U57053gi|1616674|gb|U57053.1HSU57053 3.1E−245 Human unconventional myosin-ID(MYO1F) gene, partial cds 23467 DTT11548015.1 X05332gi|35740|emb|X05332.1HSPSAR Human 0 mRNA for prostate specific antigen23468 DTT11730017.1 U14572 gi|551541|gb|U14572.1HSU14572 4.7E−90 ***ALUWARNING: Human Alu-Sp subfamily consensus sequence 23471 DTT11902028.1AK001915 gi|7023475|dbj|AK001915.1AK001915 0 Homo sapiens cDNA FLJ11053fis, clone PLACE1004664 23472 DTT11915017.1 U66062gi|1724068|gb|U66062.1HSU66062 5.9E−111 Human glp-1 receptor gene,promoter region and partial cds 23475 DTT12201062.1 M73791gi|189265|gb|M73791.1HUMNOVGENE 0 Human novel gene mRNA, complete cds23476 DTT12470020.1 AK026618 gi|10439509|dbj|AK026618.1AK026618 0 Homosapiens cDNA: FLJ22965 fis, clone KAT10418

Example 96 Members of Protein Families

SEQ ID NOS: 22001-23477 were used to conduct a profile search asdescribed in the specification above. Several of the polynucleotides ofthe invention were found to encode polypeptides having characteristicsof a polypeptide belonging to a known protein family (and thus representmembers of these protein families) and/or comprising a known functionaldomain. Table 149 (inserted prior to claims) provides: 1) the SEQ ID NO(“SEQ ID”) of the query polynucleotide sequence; 2) the sequence name(“SEQ NAME”) used as an internal identifier of the query sequence; 3)the accession number (“PFAM ID”) of the the protein family profile hit;4) a brief description of the profile hit (“PFAM DESCRIPTION”); 5) thescore (“SCORE”) of the profile hit; 6) the starting nucleotide of theprofile hit (“START”); and 7) the ending nucleotide of the profile hit(“END”). TABLE 149 SEQ ID SEQ NAME PFAM ID PFAM DESCRIPTION SCORE STARTEND 22007 2504.C11.GZ43_365848 PF00179 Ubiquitin-conjugating 92.64 4 159enzyme 22010 2504.E23.GZ43_365908 PF01260 AP endonuclease family 1 88.28222 481 22046 2505.G16.GZ43_366333 PF02594 Uncharacterized ACR, 77.64263 495 YggU family COG1872 22109 2510.N14.GZ43_369351 PF02348Cytidylyltransferase 187.84 357 675 22126 2365.D10.GZ43_345308 PF01018GTP1/OBG family 96.12 50 507 22134 2365.F24.GZ43_345370 PF00160Cyclophilin type peptidyl- 120.2 251 522 prolyl cis-trans isomerase22189 2366.L21.GZ43_345942 PF00612 IQ calmodulin-binding 33.96 415 477motif 22189 2366.L21.GZ43_345942 PF00063 Myosin head (motor 207.12 8 369domain) 22259 2368.O03.GZ43_346717 PF00160 Cyclophilin type peptidyl-120.2 242 513 prolyl cis-trans isomerase 22267 2535.C23.GZ43_370158PF02114 Phosducin 32 152 589 22334 2537.D11.GZ43_370938 PF00083 Sugar(and other) 122.88 4 288 transporter 22335 2537.D20.GZ43_370947 PF00131Metallothionein 48.56 563 665 22349 2537.N12.GZ43_371179 PF001352 KRABbox 123.24 313 498 22363 2538.B03.GZ43_371266 PF00160 Cyclophilin typepeptidyl- 117.68 320 591 prolyl cis-trans isomerase 223912554.A06.GZ43_375853 PF03015 Male sterility protein 44.96 605 749 223942554.A16.GZ43_375863 PF02348 Cytidylyltransferase 195.48 397 650 224052554.I10.GZ43_376049 PF03041 lef-2 31.88 479 536 224192565.B15.GZ43_398171 PF02271 Ubiquinol-cytochrome C 70.76 29 188reductase complex 14 kD subunit 22422 2565.C17.GZ43_398204 PF00089Trypsin 45.28 5 110 22482 2540.I17.GZ43_372216 PF00023 Ank repeat 75.44444 542 22507 2541.L08.GZ43_372663 PF00499 NADH- 54.72 89 237ubiquinone/plastoquinone oxidoreductase chain 6 225142506.C15.GZ43_366620 PF00076 RNA recognition motif. 44.44 70 276 (a.k.a.RRM, RBD, or RNP domain) 22521 2506.G24.GZ43_366725 PF00096 Zinc finger,C2H2 type 46.68 156 224 22527 2506.J20.GZ43_366793 PF00595 PDZ Domain(Also known 34.16 290 502 as DHR or GLGF). 22543 2542.D19.GZ43_372866PF00098 Zinc knuckle 46.68 224 276 22563 2542.N21.GZ43_373108 PF01545Cation efflux family 42.24 191 325 22569 2555.F16.GZ43_373295 PF02348Cytidylyltransferase 215.04 357 713 22716 2560.H21.GZ43_375268 PF00510Cytochrome c oxidase 37.28 224 436 subunit III 227212560.K10.GZ43_375329 PF01018 GTP1/OBG family 104.56 50 573 227592561.O17.GZ43_37658 PF00826 Ribosomal L10 79.88 46 180 227662456.B12.GZ43_355864 PF01545 Cation efflux family 34.16 102 236 227712456.D04.GZ43_355904 PF02114 Phosducin 30.52 139 576 228132457.J23.GZ43_356451 PF02594 Uncharacterized ACR, 77.64 189 421 YggUfamily COG1872 22818 2457.L21.GZ43_356497 PF00023 Ank repeat 38 208 30622910 2464.L02.GZ43_357946 PF00076 RNA recognition motif. 34.84 244 350a.k.a. RRM, RBD, or RNP domain) 22914 2464.N05.GZ43_357997 PF00023 Ankrepeat 128.28 491 589 22935 2465.K20.GZ43_358324 PF02594 UncharacterizedACR, 77.64 210 442 YggU family COG1872 22952 2466.I08.GZ43_360281PF00012 Hsp70 protein 120.92 16 208 22967 2467.D10.GZ43_360547 PF00008EGF-like domain 31.04 63 113 23002 2472.P22.GZ43_361231 PF00499 NADH-64.72 81 209 ubiquinone/plastoquinone oxidoreductase chain 6 230112473.I08.GZ43_361433 PF00895 ATP synthase protein 8 66.88 5 148 230392475.N08.GZ43_362321 PF00804 Syntaxin 53.08 226 601 230512480.D13.GZ43_358588 PF03025 Papillomavirus E5 33.56 583 749 230652481.B06.GZ43_358917 PF00098 Zinc knuckle 35.88 79 133 231002483.J07.GZ43_359878 PF00142 4Fe-4S iron sulfur cluster 32.8 211 288binding proteins, NifH/frxC family 23101 2483.K02.GZ43_359897 PF00160Cyclophilin type peptidyl- 117.52 244 516 prolyl cis-trans isomerase23107 2488.B07.GZ43_362475 PF01260 AP endonuclease family 1 79.88 251614 23128 2489.F09.GZ43_362957 PF02348 Cytidylyltransferase 174.36 347591 23183 2496.I06.GZ43_364281 PF02790 Cytochrome C oxidase 45.8 131 242subunit II, transmembrane domain 23207 2562.B09.GZ43_375496 PF00826Ribosomal L10 106.28 49 341 23216 2562.E14.GZ43_375573 PF00023 Ankrepeat 87.04 230 328 23225 2562.H18.GZ43_375649 PF02594 UncharacterizedACR, 65.44 206 437 YggU family COG1872 23244 2507.C03.GZ43_366992PF00083 Sugar (and other) 95.52 107 355 transporter 232672499.I09.GZ43_365436 PF00160 Cyclophilin type peptidyl- 43.24 139 238prolyl cis-trans isomerase

In addition, SEQ ID NOS:23478-23568 were also used to conduct a profilesearch as described above. Several of the polypeptides of the inventionwere found to have characteristics of a polypeptide belonging to a knownprotein family (and thus represent members of these protein families)and/or comprising a known functional domain. Table 150 (inserted priorto claims) provides: 1) the SEQ ID NO (“SEQ ID”) of the query proteinsequence; 2) the sequence name (“PROTEIN SEQ NAME”) used as an internalidentifier of the query sequence; 3) the accession number (“PFAM ID”) ofthe the protein family profile hit; 4) a brief description of theprofile hit (“PFAM DESCRIPTION”); 5) the score (“SCORE”) of the profilehit; 6) the starting residue of the profile hit (“START”); and 7) theending residue of the profile hit (“END”).

Some SEQ ID NOS exhibited multiple profile hits where the query sequencecontains overlapping profile regions, and/or where the sequence containstwo different functional domains. Each of the profile hits of Tables 8and 9 is described in more detail below. The acronyms for the profiles(provided in parentheses) are those used to identify the profile in thePfam, Prosite, and InterPro databases. The Pfam database can be accessedthrough web sites supported by Genome Sequencing Center at theWashington University School of Medicine or by the European MolecularBiology Laboratories in Heidelberg, Germany. The Prosite database can beaccessed at the ExPASy Molecular Biology Server on the internet. TheInterPro database can be accessed at a web site supported by the EMBLEuropean Bioinformatics Institute. The public information available onthe Pfam, Prosite, and InterPro databases regarding the variousprofiles, including but not limited to the activities, function, andconsensus sequences of various proteins families and protein domains, isincorporated herein by reference. TABLE 150 PROTEIN SEQ SEQ ID NAME PFAMID PFAM DESCRIPTION SCORE START END 23481 DTP00514038.1 PF00587 tRNAsynthetase class II core 33.42 1 116 domain (G, H, P, S and T) 23482DTP00740019.1 PF00012 Hsp70 protein 948.22 27 564 23484 DTP01169031.1PF00023 Ank repeat 159.66 82 114 23484 DTP01169031.1 PF00023 Ank repeat159.66 181 213 23484 DTP01169031.1 PF00023 Ank repeat 159.66 148 18023484 DTP01169031.1 PF00023 Ank repeat 159.66 115 147 23484DTP01169031.1 PF00023 Ank repeat 159.66 82 114 23484 DTP01169031.1PF00023 Ank repeat 159.66 49 81 23484 DTP01169031.1 PF00023 Ank repeat159.66 16 48 23484 DTP01169031.1 PF00023 Ank repeat 159.66 181 213 23484DTP01169031.1 PF00023 Ank repeat 159.66 115 147 23484 DTP01169031.1PF00023 Ank repeat 159.66 49 81 23484 DTP01169031.1 PF00023 Ank repeat159.66 16 48 23484 DTP01169031.1 PF00023 Ank repeat 159.66 148 180 23486DTP01315019.1 PF01839 FG-GAP repeat 255.09 427 479 23486 DTP01315019.1PF01839 FG-GAP repeat 255.09 49 111 23486 DTP01315019.1 PF01839 FG-GAPrepeat 255.09 248 300 23486 DTP01315019.1 PF01839 FG-GAP repeat 255.09303 362 23486 DTP01315019.1 PF01839 FG-GAP repeat 255.09 365 424 23495DTP02737026.1 PF01423 Sm protein 31.6 19 66 23496 DTP02850014.1 PF00804Syntaxin 156.59 1 292 23496 DTP02850014.1 PF00804 Syntaxin 156.59 1 29223496 DTP02850014.1 PF00804 Syntaxin 156.59 1 292 23510 DTP04403022.1PF00400 WD domain, G-beta repeat 35.93 80 116 23510 DTP04403022.1PF00400 WD domain, G-beta repeat 35.93 38 74 23510 DTP04403022.1 PF00400WD domain, G-beta repeat 35.93 1 33 23512 DTP04660026.1 PF00083 Sugar(and other) transporter 234.43 1 484 23512 DTP04660026.1 PF00083 Sugar(and other) transporter 234.43 1 484 23518 DTP05742038.1 PF01018GTP1/OBG family 133.76 105 208 23518 DTP05742038.1 PF01018 GTP1/OBGfamily 133.76 7 97 23518 DTP05742038.1 PF01018 GTP1/OBG family 133.76105 208 23518 DTP05742038.1 PF01018 GTP1/OBG family 133.76 7 97 23518DTP05742038.1 PF01018 GTP1/OBG family 133.76 105 208 23518 DTP05742038.1PF01018 GTP1/OBG family 133.76 7 97 23519 DTP06137039.1 PF02271Ubiquinol-cytochrome C 141.38 4 154 reductase complex 14 kD subunit23521 DTP06706028.1 PF00054 Laminin G domain 63.34 56 178 23521DTP06706028.1 PF00054 Laminin G domain 63.34 281 292 23523 DTP07040024.1PF00640 Phosphotyrosine interaction 233.89 461 618 domain (PTB/PID).23523 DTP07040024.1 PF00595 PDZ domain (Also known as 85.47 656 742 DHRor GLGF). 23532 DTP08249031.1 PF00515 TPR Domain 115 4 37 23532DTP08249031.1 PF00515 TPR Domain 115 72 105 23532 DTP08249031.1 PF00515TPR Domain 115 38 71 23532 DTP08249031.1 PF00515 TPR Domain 115 259 29223532 DTP08249031.1 PF00515 TPR Domain 115 300 333 23532 DTP08249031.1PF00515 TPR Domain 115 225 258 23535 DTP08527022.1 PF02348Cytidylyltransferase 48.59 1 166 23535 DTP08527022.1 PF02348Cytidylyltransferase 48.59 1 166 23535 DTP08527022.1 PF02348Cytidylyltransferase 48.59 1 166 23535 DTP08527022.1 PF02348Cytidylyltransferase 48.59 1 166 23536 DTP08595029.1 PF00400 WD domain,G-beta repeat 80.04 183 221 23536 DTP08595029.1 PF00400 WD domain,G-beta repeat 80.04 236 273 23536 DTP08595029.1 PF00400 WD domain,G-beta repeat 80.04 365 402 23536 DTP08595029.1 PF00400 WD domain,G-beta repeat 80.04 279 316 23536 DTP08595029.1 PF00400 WD domain,G-beta repeat 80.04 325 357 23537 DTP08711028.1 PF00023 Ank repeat 81.9622 54 23537 DTP08711028.1 PF00023 Ank repeat 81.96 55 87 23538DTP08773029.1 PF00183 Hsp90 protein 100.71 104 173 23540 DTP09387027.1PF00069 Protein kinase domain 224.56 76 342 23545 DTP09742018.1 PF01545Cation efflux family 368.71 114 418 23545 DTP09742018.1 PF01545 Cationefflux family 368.71 114 418 23548 DTP09796037.1 PF00612 IQcalmodulin-binding motif 87.63 879 899 23548 DTP09796037.1 PF00612 IQcalmodulin-binding motif 87.63 856 876 23548 DTP09796037.1 PF00612 IQcalmodulin-binding motif 87.63 831 851 23548 DTP09796037.1 PF00612 IQcalmodulin-binding motif 87.63 808 828 23548 DTP09796037.1 PF00612 IQcalmodulin-binding motif 87.63 780 800 23548 DTP09796037.1 PF00612 IQcalmodulin-binding motif 87.63 757 777 23548 DTP09796037.1 PF01843 DILdomain 125.23 1574 1679 23548 DTP09796037.1 PF00063 Myosin head (motordomain) 1228.24 69 741 23550 DTP10360049.1 PF00168 C2 domain 50.07 26114 23550 DTP10360049.1 PF00168 C2 domain 50.07 228 315 23551DTP10539025.1 PF00595 PDZ domain (Also known as 32.34 5 84 DHR or GLGF).23553 DTP10683050.1 PF00467 KOW motif 89.22 49 107 23556 DTP11479027.1PF00096 Zinc finger, C2H2 type 209.31 402 424 23556 DTP11479027.1PF01352 KRAB box 134.58 8 70 23556 DTP11479027.1 PF00096 Zinc finger,C2H2 type 209.31 374 396 23556 DTP11479027.1 PF00096 Zinc finger, C2H2type 209.31 346 368 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type209.31 318 340 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31290 312 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31 262284 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31 234 25623556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31 206 228 23557DTP11483021.1 PF00063 Myosin head (motor domain) 339.24 117 271 23557DTP11483021.1 PF00063 Myosin head (motor domain) 339.24 34 115 23558DTP11548024.1 PF00089 Trypsin 272.53 25 253 23564 DTP11966049.1 PF00023Ank repeat 165.68 49 81 23564 DTP11966049.1 PF00023 Ank repeat 165.68148 180 23564 DTP11966049.1 PF00023 Ank repeat 165.68 181 214 23564DTP11966049.1 PF00023 Ank repeat 165.68 148 180 23564 DTP11966049.1PF00023 Ank repeat 165.68 115 147 23564 DTP11966049.1 PF00023 Ank repeat165.68 82 114 23564 DTP11966049.1 PF00023 Ank repeat 165.68 49 81 23564DTP11966049.1 PF00023 Ank repeat 165.68 181 214 23564 DTP11966049.1PF00023 Ank repeat 165.68 181 214 23564 DTP11966049.1 PF00023 Ank repeat165.68 16 48 23564 DTP11966049.1 PF00023 Ank repeat 165.68 115 147 23564DTP11966049.1 PF00023 Ank repeat 165.68 82 114 23564 DTP11966049.1PF00023 Ank repeat 165.68 16 48 23564 DTP11966049.1 PF00023 Ank repeat165.68 148 180 23564 DTP11966049.1 PF00023 Ank repeat 165.68 115 14723564 DTP11966049.1 PF00023 Ank repeat 165.68 82 114 23564 DTP11966049.1PF00023 Ank repeat 165.68 49 81 23564 DTP11966049.1 PF00023 Ank repeat165.68 16 48 23566 DTP12201071.1 PF00826 Ribosomal L10 467.36 1 17623566 DTP12201071.1 PF00826 Ribosomal L10 467.36 1 176

Example 97 Detection of Differential Expression Using Arrays and Sourceof Patient Tissue Samples

mRNA isolated from samples of cancerous and normal breast, colon, andprostate tissue obtained from patients were analyzed to identify genesdifferentially expressed in cancerous and normal cells. Normal andcancerous tissues were collected from patients using laser capturemicrodissection (LCM) techniques, which techniques are well known in theart (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran etal. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999)Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6;Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al.(1996) Science 274:998-1001).

Table 151 (inserted prior to claims) provides information about eachpatient from which colon tissue samples were isolated, including: thePatient ID (“PT ID”) and Path ReportID (“Path ID”), which are numbersassigned to the patient and the pathology reports for identificationpurposes; the group (“Grp”) to which the patients have been assigned;the anatomical location of the tumor (“Anatom Loc”); the primary tumorsize (“Size”); the primary tumor grade (“Grade”); the identification ofthe histopathological grade (“Histo Grade”); a description of localsites to which the tumor had invaded (“Local Invasion”); the presence oflymph node metastases (“Lymph Met”); the incidence of lymph nodemetastases (provided as a number of lymph nodes positive for metastasisover the number of lymph nodes examined) (“Lymph Met Incid”); theregional lymphnode grade (“Reg Lymph Grade”); the identification ordetection of metastases to sites distant to the tumor and their location(“Dist Met & Loc”); the grade of distant metastasis (“Dist Met Grade”);and general comments about the patient or the tumor (“Comments”).Histophatology of all primary tumors incidated the tumor wasadenocarcinmoa except for Patient ID Nos. 130 (for which no informationwas provided), 392 (in which greater than 50% of the cells were mucinouscarcinoma), and 784 (adenosquamous carcinoma). Extranodal extensionswere described in three patients, Patient ID Nos. 784, 789, and 791.Lymphovascular invasion was described in Patient ID Nos. 128, 278, 517,534, 784, 786, 789, 791, 890, and 892. Crohn's-like infiltrates weredescribed in seven patients, Patient ID Nos. 52, 264, 268, 392, 393,784, and 791.

Table 152 below provides information about each patient from which theprostate tissue samples were isolated, including: 1) the “Patient ID”,which is a number assigned to the patient for identification purposes;2) the “Tissue Type”; and 3) the “Gleason Grade” of the tumor.Histopathology of all primary tumors indicated the tumor wasadenocarcinoma. TABLE 152 Prostate patient data. Gleason Patient IDTissue Type Grade 93 Prostate Cancer 3 + 4 94 Prostate Cancer 3 + 3 95Prostate Cancer 3 + 3 96 Prostate Cancer 3 + 3 97 Prostate Cancer 3 + 2100 Prostate Cancer 3 + 3 101 Prostate Cancer 3 + 3 104 Prostate Cancer3 + 3 105 Prostate Cancer 3 + 4 106 Prostate Cancer 3 + 3 138 ProstateCancer 3 + 3 151 Prostate Cancer 3 + 3 153 Prostate Cancer 3 + 3 155Prostate Cancer 4 + 3 171 Prostate Cancer 3 + 4 173 Prostate Cancer 3 +4 231 Prostate Cancer 3 + 4 232 Prostate Cancer 3 + 3 251 ProstateCancer 3 + 4 282 Prostate Cancer 4 + 3 286 Prostate Cancer 3 + 3 294Prostate Cancer 3 + 4 351 Prostate Cancer 5 + 4 361 Prostate Cancer 3 +3 362 Prostate Cancer 3 + 3 365 Prostate Cancer 3 + 2 368 ProstateCancer 3 + 3 379 Prostate Cancer 3 + 4 388 Prostate Cancer 5 + 3 391Prostate Cancer 3 + 3 420 Prostate Cancer 3 + 3 425 Prostate Cancer 3 +3 428 Prostate Cancer 4 + 3 431 Prostate Cancer 3 + 4 492 ProstateCancer 3 + 3 493 Prostate Cancer 3 + 4 496 Prostate Cancer 3 + 3 510Prostate Cancer 3 + 3 511 Prostate Cancer 4 + 3 514 Prostate Cancer 3 +3 549 Prostate Cancer 3 + 3 552 Prostate Cancer 3 + 3 858 ProstateCancer 3 + 4 859 Prostate Cancer 3 + 4 864 Prostate Cancer 3 + 4 883Prostate Cancer 4 + 4 895 Prostate Cancer 3 + 3 901 Prostate Cancer 3 +3 909 Prostate Cancer 3 + 3 921 Prostate Cancer 3 + 3 923 ProstateCancer 4 + 3 934 Prostate Cancer 3 + 3 1134 Prostate Cancer 3 + 4 1135Prostate Cancer 3 + 3 1136 Prostate Cancer 3 + 4 1137 Prostate Cancer3 + 3 1138 Prostate Cancer 4 + 3

Table 153 provides information about each patient from which the breasttissue samples were isolated, including: 1) the “Pat Num”, a numberassigned to the patient for identification purposes; 2) the “Histology”,which indicates whether the tumor was characterized as an intraductalcarcinoma (IDC) or ductal carcinoma in situ (DCIS); 3) the incidence oflymph node metastases (LMF), represented as the number of lymph nodespositive to metastases out of the total number examined in the patient;4) the “Tumor Size”; 5) “TNM Stage”, which provides the tumor grade(T#), where the number indicates the grade and “p” indicates that thetumor grade is a pathological classification; regional lymph nodemetastasis (N#), where “0” indicates no lymph node metastases werefound, “1” indicates lymph node metastases were found, and “X” meansinformation not available and; the identification or detection ofmetastases to sites distant to the tumor and their location (M#), with“X” indicating that no distant mesatses were reported; and the stage ofthe tumor (“Stage Grouping”). “nr” indicates “no reported”. TABLE 153Breast cancer patient data Pat Tumor Stage Num Histology LMF Size TNMStage Grouping 280 IDC, DCIS + D2 nr 2 cm T2NXMX probable Stage II 284IDC, DCIS 0/16 2 cm T2pN0MX Stage II 285 IDC, DCIS nr 4.5 cm T2NXMXprobable Stage II 291 IDC, DCIS 0/24 4.5 cm T2pN0MX Stage II 302 IDC,DCIS nr 2.2 cm T2NXMX probable Stage II 375 IDC, DCIS nr 1.5 cm T1NXMXprobable Stage I 408 IDC 0/23 3.0 cm T2pN0MX Stage II 416 IDC 0/6 3.3 cmT2pN0MX Stage II 421 IDC, DCIS nr 3.5 cm T2NXMX probable Stage II 459IDC 2/5 4.9 cm T2pN1MX Stage II 465 IDC 0/10 6.5 cm T3pN0MX Stage II 470IDC, DCIS 0/6 2.5 cm T2pN0MX Stage II 472 IDC, DCIS 6/45 5.0+ cm T3pN1MXStage III 474 IDC 0/18 6.0 cm T3pN0MX Stage II 476 IDC 0/16 3.4 cmT2pN0MX Stage II 605 IDC, DCIS 1/25 5.0 cm T2pN1MX Stage II 649 IDC,DCIS 1/29 4.5 cm T2pN1MX Stage II

Identification of Differentially Expressed Genes

cDNA probes were prepared from total RNA isolated from the patient cellsdescribed above. Since LCM provides for the isolation of specific celltypes to provide a substantially homogeneous cell sample, this providedfor a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primercontaining a T7 RNA polymerase promoter, followed by second strand DNAsynthesis. cDNA was then transcribed in vitro to produce antisense RNAusing the T7 promoter-mediated expression (see, e.g., Luo et al. (1999)Nature Med 5:117-122), and the antisense RNA was then converted intocDNA. The second set of cDNAs were again transcribed in vitro, using theT7 promoter, to provide antisense RNA. Optionally, the RNA was againconverted into cDNA, allowing for up to a third round of T7-mediatedamplification to produce more antisense RNA. Thus the procedure providedfor two or three rounds of in vitro transcription to produce the finalRNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to theantisense RNA mix, and producing fluorescently labeled cDNA from the RNAstarting material. Fluorescently labeled cDNAs prepared from the tumorRNA sample were compared to fluorescently labeled cDNAs prepared fromnormal cell RNA sample. For example, the cDNA probes from the normalcells were labeled with Cy3 fluorescent dye (green) and the cDNA probesprepared from the tumor cells were labeled with Cy5 fluorescent dye(red), and vice versa.

Each array used had an identical spatial layout and control spot set.Each microarray was divided into two areas, each area having an arraywith, on each half, twelve groupings of 32×12 spots, for a total ofabout 9,216 spots on each array. The two areas are spotted identicallywhich provide for at least two duplicates of each clone per array.

Polynucleotides for use on the arrays were obtained from both publiclyavailable sources and from cDNA libraries generated from selected celllines and patient tissues. PCR products of from about 0.5 kb to 2.0 kbamplified from these sources were spotted onto the array using aMolecular Dynamics Gen III spotter according to the manufacturer'srecommendations. The first row of each of the 24 regions on the arrayhad about 32 control spots, including 4 negative control spots and 8test polynucleotides. The test polynucleotides were spiked into eachsample before the labeling reaction with a range of concentrations from2-600 pg/slide and ratios of 1:1. For each array design, two slides werehybridized with the test samples reverse-labeled in the labelingreaction. This provided for about four duplicate measurements for eachclone, two of one color and two of the other, for each sample.

The differential expression assay was performed by mixing equal amountsof probes from tumor cells and normal cells of the same patient. Thearrays were prehybridized by incubation for about 2 hrs at 60° C. in5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twicein isopropanol. Following prehybridization of the array, the probemixture was then hybridized to the array under conditions of highstringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS.After hybridization, the array was washed at 55° C. three times asfollows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2%SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using aMolecular Dynamics Generation III dual color laser-scanner/detector. Theimages were processed using BioDiscovery Autogene software, and the datafrom each scan set normalized to provide for a ratio of expressionrelative to normal. Data from the microarray experiments was analyzedaccording to the algorithms described in U.S. application Ser. No.60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M.Randazzo, and entitled “Precision and accuracy in cDNA microarray data,”which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with theopposite color in order to perform the assay in both “color directions.”Each experiment was sometimes repeated with two more slides (one in eachcolor direction). The level fluorescence for each sequence on the arrayexpressed as a ratio of the geometric mean of 8 replicate spots/genesfrom the four arrays or 4 replicate spots/gene from 2 arrays or someother permutation. The data were normalized using the spiked positivecontrols present in each duplicated area, and the precision of thisnormalization was included in the final determination of thesignificance of each differential. The fluorescent intensity of eachspot was also compared to the negative controls in each duplicated areato determine which spots have detected significant expression levels ineach sample.

A statistical analysis of the fluorescent intensities was applied toeach set of duplicate spots to assess the precision and significance ofeach differential measurement, resulting in a p-value testing the nullhypothesis that there is no differential in the expression level betweenthe tumor and normal samples of each patient. During initial analysis ofthe microarrays, the hypothesis was accepted if p>10⁻³, and thedifferential ratio was set to 1.000 for those spots. All other spotshave a significant difference in expression between the tumor and normalsample. If the tumor sample has detectable expression and the normaldoes not, the ratio is truncated at 1000 since the value for expressionin the normal sample would be zero, and the ratio would not be amathematically useful value (e.g., infinity). If the normal sample hasdetectable expression and the tumor does not, the ratio is truncated to0.001, since the value for expression in the tumor sample would be zeroand the ratio would not be a mathematically useful value. These lattertwo situations are referred to herein as “on/off.” Database tables werepopulated using a 95% confidence level (p>0.05).

Table 154 (inserted prior to claims) provides the results for geneproducts expressed by at least 2-fold or greater in cancerous prostate,colon, or breast tissue samples relative to normal tissue samples in atleast 20% of the patients tested. Table 154 includes: 1) the SEQ ID NO(“SEQ ID”) assigned to each sequence for use in the presentspecification; 2) the Cluster Identification No. (“CLUSTER”); 3) thepercentage of patients tested in which expression levels (e.g., asmessage level) of the gene was at least 2-fold greater in cancerousbreast tissue than in matched normal tissue (“BREAST PATIENTS >=2×”); 4)the percentage of patients tested in which expression levels (e.g., asmessage level) of the gene was less than or equal to ½ of the expressionlevel in matched normal breast cells (“BREAST PATIENTS <=halfx”); 5) thepercentage of patients tested in which expression levels (e.g., asmessage level) of the gene was at least 2-fold greater in cancerouscolon tissue than in matched normal tissue (“COLON PATIENTS >=2×”); 6)the percentage of patients tested in which expression levels (e.g., asmessage level) of the gene was less than or equal to ½ of the expressionlevel in matched normal colon cells (“COLON PATIENTS <=halfx”); 7) thepercentage of patients tested in which expression levels (e.g., asmessage level) of the gene was at least 2-fold greater in cancerousprostate tissue than in matched normal tissue (“PROSTATEPATIENTS >=2×”); and 8) the percentage of patients tested in whichexpression levels (e.g., as message level) of the gene was less than orequal to ½ of the expression level in matched normal prostate cells(“PROSTATE PATIENTS <=halfx”).

These data provide evidence that the genes represented by thepolynucleotides having the indicated sequences are differentiallyexpressed in breast cancer as compared to normal non-cancerous breasttissue, are differentially expressed in colon cancer as compared tonormal non-cancerous colon tissue, and are differentially expressed inprostate cancer as compared to normal non-cancerous prostate tissue.TABLE 154 BREAST BREAST COLON COLON PROSTATE PROSTATE PATIENTS >=PATIENTS <= PATIENTS >= PATIENTS <= PATIENTS >= PATIENTS <= SEQ ID CLONEID 2x halfx 2x halfx 2x halfx 22004 M00072944A:C07 35 22008M00072947B:G04 32.5 22009 M00072947D:G05 27.5 22015 M00072963B:G11 4022016 M00072967A:G07 25 22018 M00072968A:F08 22.5 22020 M00072968D:E0532.5 22021 M00072970C:B07 25 22024 M00072971C:B07 22.5 22028M00072975A:D11 23.5 22034 M00073001A:F07 27.5 22038 M00073003A:E06 42.522039 M00073003B:E10 27.5 22042 M00073006A:H08 23.5 22043 M00073006C:D0727.5 22045 M00073009B:C08 32.5 52.4 22048 M00073013A:D10 32.5 22049M00073013A:F10 20 22050 M00073013C:B10 32.5 22052 M00073014D:F01 4022054 M00073015A:H06 47.5 22061 M00073020C:F07 32.5 22062 M00073020D:C0637.5 22063 M00073021C:E04 30 22071 M00073030B:C02 22.5 22072M00073030C:A02 20 22073 M00073036C:H10 25 22086 M00073043D:H09 32.522090 M00073044C:G12 32.5 22094 M00073045C:E06 22.5 22096 M00073045D:B0430 22105 M00073048C:B01 20 22107 M00073049A:H04 27.5 49.2 22108M00073049B:B03 23.5 40 31.7 22109 M00073049B:B06 20 22110 M00073049C:C0920 22136 M00073066C:D02 27.5 22142 M00073070B:B06 32.5 22146M00073074D:A04 20 22153 M00073086D:B05 30 22156 M00073091B:C04 20 22163M00073424D:C03 52.9 22171 M00073403C:C10 30 22173 M00073403C:E11 29.452.5 22176 M00073412C:E07 30 22177 M00073435C:E06 27.5 22178M00073412D:B07 35.3 42.5 22189 M00073430C:B02 32.5 22196 M00073442A:F0725 22197 M00073442B:D12 27.5 20.6 22199 M00073446C:A03 22.5 22201M00073447D:F01 45 38.1 22204 M00073453C:C09 41.2 22212 M00073469B:A0927.5 36.5 22216 M00073474C:F08 30 22.2 22220 M00073484B:A05 23.5 30 22.222228 M00073497C:D03 29.4 30 22233 M00073513A:G07 23.5 25.4 22236M00073517A:A06 32.5 22241 M00073529A:F03 20 22242 M00073530B:A02 20 54.022243 M00073531B:H02 50.8 22246 M00073539C:H05 27.5 22247 M00073541B:C1030 22248 M00073547B:F04 22.5 22249 M00073547C:D02 35 22256M00073554B:D11 37.5 22264 M00073568A:G06 32.5 22265 M00073568C:G07 2522269 M00073576B:E03 22.5 22270 M00073576C:C11 20 22273 M00073580A:D0832.5 22280 M00073598D:E11 40 22284 M00073601D:D08 32.5 22286M00073603B:C03 30 22288 M00073603C:C02 76.5 67.5 22290 M00073604B:B07 3022294 M00073605B:F11 58.8 22299 M00073614C:F06 60 22300 M00073615D:E0382.5 22301 M00073616A:F06 32.5 28.6 22304 M00073621D:A04 27.5 22316M00073633D:A04 23.5 52.5 22318 M00073634C:H08 23.5 85 39.7 22319M00073635D:C10 35.3 22323 M00073638A:A12 47.5 22325 M00073639A:G08 27.522340 M00073651C:F06 29.4 27.5 36.5 22342 M00073652D:B11 64.7 70 22343M00073655B:A04 37.5 22353 M00073669A:F04 20 22354 M00073669B:E12 23.527.5 22357 M00073687A:D11 50 22.2 22361 M00073672D:E09 35 42.9 22367M00073677B:F01 32.5 22369 M00073678B:H02 35 22372 M00073681A:F12 29.425.4 22377 M00073689C:C09 41.3 22382 M00073696C:D11 35.3 22384M00073697C:F11 29.4 34.9 22388 M00073700B:D12 30 22390 M00073708D:E1023.8 22392 M00073709B:F01 25 22394 M00073709C:A02 22.5 22398M00073713D:E07 27.5 22399 M00073715A:F05 20 31.7 22400 M00073715B:B0637.5 27.0 22401 M00073717C:A12 37.5 22403 M00073720D:H11 27.5 20.6 22408M00073735C:E04 23.8 22413 M00073743C:F03 25 22417 M00073748B:F07 3522424 M00073754B:D05 37.5 22436 M00073765A:E02 32.5 22439 M00073766B:B0722.5 22442 M00073772B:E07 22.2 22450 M00073779B:B11 32.5 22462M00073798A:H03 35 22464 M00073801B:A10 35 22467 M00073809C:E09 23.5 4525.4 22469 M00073813D:B06 27.0 22470 M00073814C:B04 71.4 22473M00073790A:A12 36.5 22480 M00073799A:G02 37.5 22481 M00073799D:G04 3022486 M00073813A:E06 32.5 22487 M00073813B:A01 30 22493 M00073822C:E0235 22494 M00073824A:C04 38.1 22497 M00073832A:A06 20 20.6 22500M00073834A:H10 35 22502 M00073834D:H06 25 31.7 22503 M00073836D:E05 23.822506 M00073838B:F09 25 22509 M00073839A:D05 23.5 47.5 41.3 22513M00073850A:H09 54.0 22532 M00073867D:F10 36.5 22533 M00073871B:C12 32.522534 M00073872C:B09 22.5 22535 M00073872D:B01 32.5 22536 M00073872D:E1022.5 22544 M00073883B:D03 22.5 22550 M00073892B:F12 32.5 22555M00073905B:A03 55.6 22562 M00073897B:B11 30 22564 M00073899A:D06 32.522565 M00073911B:G10 23.8 22567 M00073916A:B07 42.5 23.8 22572M00073923C:A04 29.4 22.5 22575 M00073931D:E02 27.5 22577 M00073936D:E0525 22579 M00073908C:D09 40 27.0 22599 M00073944D:A07 27.5 22620M00073968B:B06 27.5 57.1 22625 M00073979C:G07 37.5 44.4 22634M00073988D:F09 38.1 22641 M00073979B:B05 27.5 66.7 22645 M00073988C:G0840 22654 M00074011D:C05 42.5 22656 M00074013C:C09 20 22659M00074015A:C03 22.5 22665 M00074020D:G10 40 22669 M00074025A:F06 25 36.522670 M00074025B:A12 20.6 22671 M00074026C:H09 32.5 22687 M00074053C:E0525.0 30 22695 M00074059B:G10 27.5 22703 M00074075B:A09 27.5 22706M00074079A:E07 42.5 31.7 22708 M00074084D:B04 33.3 22710 M00074085B:E0623.8 22712 M00074087B:C09 28.6 22713 M00074087C:G05 23.8 22717M00074089D:E03 20 54.0 22720 M00074093B:A03 23.5 27.5 22722M00074094B:F10 52.4 22723 M00074096D:G12 25.4 22726 M00074098C:B09 23.822727 M00074099C:B09 20 22729 M00074101D:D07 35 22730 M00074102A:C0437.5 22733 M00074107C:C08 35 22741 M00074131A:H09 37.5 27.0 22742M00074132C:F10 32.5 22.2 22747 M00074138D:A08 45 22.2 22749M00074142B:C11 32.5 22750 M00074142D:A10 22.5 22753 M00074122A:B02 37.522756 M00074132A:E11 22.5 22757 M00074132B:B07 35 20.6 22758M00074134A:G11 27.5 22759 M00074149A:B10 41.2 47.5 22762 M00074153D:A0537.5 22765 M00074157C:G08 25 22767 M00074158C:F12 37.5 22769M00074159C:A05 25 22777 M00074174A:C02 27.5 27.0 22782 M00074177B:H08 3522785 M00074179C:B01 27.5 28.6 22787 M00074184D:B01 37.5 28.6 22789M00074191C:D08 57.1 22790 M00074192C:C10 33.3 22793 M00074198C:A12 29.445 31.7 22794 M00074198D:D10 36.5 22800 M00074203D:F01 40 22802M00074206A:H12 40 22.2 22806 M00074208B:F09 22.5 41.3 22811M00074215A:F09 42.5 22813 M00074216D:H03 35 22819 M00074223B:D12 3022821 M00074225A:H12 25 22827 M00074234A:C05 30 22830 M00074234D:F1237.5 22834 M00074242D:F09 25 22837 M00074247B:G11 27.5 22839M00074248C:E12 25.4 22840 M00074249C:B11 27.5 22846 M00074251C:E03 3522849 M00074253C:F03 32.5 22850 M00074255B:A01 20 22851 M00074258A:H1232.5 22861 M00074271B:E11 25 22869 M00074280D:H03 20 31.7 22870M00074284B:B03 27.5 25.4 22873 M00074288A:F11 45 20.6 22874M00074290A:G10 37.5 22875 M00074290C:B05 20.6 22877 M00074293D:B05 2022878 M00074293D:H07 32.5 22882 M00074304B:C09 22.5 39.7 22883M00074304D:D07 36.5 22884 M00074306A:B09 27.5 22886 M00074310D:D02 3525.4 22888 M00074315B:A03 22.5 22892 M00074835A:H10 40 22893M00074835B:F12 22.5 22895 M00074837A:E01 35 22899 M00074843D:D02 25 65.122900 M00074844B:B02 58.8 20 22901 M00074844D:F09 30 20.6 22905M00074847B:G03 30 22909 M00074852B:A02 37.5 22912 M00074854A:C11 4022913 M00074855B:A05 27.5 22917 M00074863D:F07 27.5 22919 M00074317D:B0820.6 22920 M00074320C:A06 54.0 22921 M00074865A:F05 20 50.8 22923M00074871C:G05 20 22926 M00074879A:A02 35 22.2 22930 M00074890A:E03 2020.6 22931 M00074895D:H12 20.6 22934 M00074901C:E05 27.5 22938M00074905D:A01 35 30.2 22941 M00074912B:A10 65.1 22943 M00074916A:H03 3022949 M00074927D:G09 22.5 22954 M00074936B:E10 37.5 22955 M00074939B:A0632.5 22959 M00074966D:E08 34.9 22962 M00074974C:E11 22.2 22964M00074954A:H06 20 22975 M00072985A:C12 20 22981 M00072996B:A10 27.5 20.622984 M00072997D:H06 40 20.6 22986 M00074333D:A11 41.2 47.5 22990M00074343C:A03 30 22998 M00074366A:H07 27.5 42.9 23004 M00074392C:D0232.5 23006 M00074417D:F07 23.5 67.5 23008 M00074406B:F10 27.5 23012M00074391B:D02 27.5 23019 M00074461D:E04 47.5 25.4 23025 M00074488C:C0832.5 23027 M00074501A:G07 49.2 23029 M00074515A:E02 25.4 23030M00074515C:A11 32.5 23031 M00074516B:H03 23.8 23032 M00074525A:B05 20.623039 M00074561D:D12 30 28.6 23040 M00074566B:A04 35 23044M00074555A:E10 27.5 23045 M00074561A:B09 40 23052 M00074582D:B09 25.423057 M00074596D:B12 20 22.2 23058 M00074606C:G02 29.4 23064M00074628C:D03 37.5 23067 M00074637A:C02 20 23068 M00074638D:C12 29.4 3523069 M00074639A:C08 30 23073 M00074662B:A05 35.3 23078 M00074676D:H0722.5 23080 M00074681D:A02 32.5 23082 M00074699B:C03 32.5 23083M00074701D:H09 25 23086 M00074713B:F02 20 39.7 23089 M00074723D:D05 27.523092 M00074740B:F06 27.5 23095 M00074752A:D08 32.5 20.6 23099M00074765D:F06 40 23102 M00074773C:G03 20 23103 M00074774A:D03 31.723105 M00074780C:C02 20 23110 M00075000A:D06 32.5 23117 M00074800B:H0135 23120 M00074825C:E06 30 23122 M00075018A:G04 30 23134 M00075035C:C0932.5 23135 M00075045D:H03 25 23145 M00075153C:C11 22.5 23146M00075161A:E05 30 23152 M00075152D:C06 30 23155 M00075160A:E04 42.523163 M00075174D:D06 27.5 23167 M00075199D:D11 29.4 36.5 23168M00075201D:A05 30 23169 M00075203A:G06 35 20.6 23179 M00075245A:A06 41.237.5 28.6 23189 M00075283A:F04 34.9 23198 M00075329B:E10 25.0 62.5 23203M00075344D:A08 22.5 23224 M00075379A:E07 27.5 23225 M00075383A:B11 2523227 M00075409A:E04 25 23235 M00075448B:G11 35 20.6 23239M00075460C:B06 35.3 62.5 20.6 23245 M00075504B:A10 32.5 23250M00075514A:G12 32.5 23266 M00075621A:F06 20 20.6 23386 23.5 23387 34.323388 23.5 67.5 23390 35.3 26.1 23400 32.5 23402 41.3 23403 23404 30.028.6 23426 36.6 23427 42.9 38.2 23429 31.6 23434 55.0 23438 21.3 21.523439 30.0 23444 23445 27.5 23447 29.4 32.6 23449 35.3 60.9 23461 29.423462 41.2 36.2 23463 27.5 23472 23.4 23474 37.5 23475 35.3 54.3

Example 98 Antisense Regulation of Gene Expression

The expression of the differentially expressed genes represented by thepolynucleotides in the cancerous cells can be further analyzed usingantisense knockout technology to confirm the role and function of thegene product in tumorigenesis, e.g., in promoting a metastaticphenotype.

Methods for analysis using antisense technology are well known in theart. For example, a number of different oligonucleotides complementaryto the mRNA generated by the differentially expressed genes identifiedherein can be designed as antisense oligonucleotides, and tested fortheir ability to suppress expression of the genes. Sets of antisenseoligomers specific to each candidate target are designed using thesequences of the polynucleotides corresponding to a differentiallyexpressed gene and the software program HYBsimulator Version 4(available for Windows 95/Windows NT or for Power Macintosh, RNAture,Inc. 1003 Health Sciences Road, West, Irvine, Calif. 92612 USA). Factorsconsidered when designing antisense oligonucleotides include: 1) the Theexpression of the differentially expressed genes represented by thepolynucleotides in the cancerous cells can be analyzed using antisenseknockout technology to confirm the role and function of the gene productin tumorigenesis, e.g., in promoting a metastatic phenotype.

A number of different oligonucleotides complementary to the mRNAgenerated by the differentially expressed genes identified herein can bedesigned as potential antisense oligonucleotides, and tested for theirability to suppress expression of the genes. Sets of anti senseoligomers specific to each candidate target are designed using thesequences of the polynucleotides corresponding to a differentiallyexpressed gene and the software program HYBsimulator Version 4(available for Windows 95/Windows NT or for Power Macintosh, RNAture,Inc. 1003 Health Sciences Road, West, Irvine, Calif. 92612 USA). Factorsthat are considered when designing antisense oligonucleotidesinclude: 1) the secondary structure of oligonucleotides; 2) thesecondary structure of the target gene; 3) the specificity with no orminimum cross-hybridization to other expressed genes; 4) stability; 5)length and 6) terminal GC content. The antisense oligonucleotide isdesigned so that it will hybridize to its target sequence underconditions of high stringency at physiological temperatures (e.g., anoptimal temperature for the cells in culture to provide forhybridization in the cell, e.g., about 37° C.), but with minimalformation of homodimers.

Using the sets of oligomers and the HYBsimulator program, three to tenantisense oligonucleotides and their reverse controls are designed andsynthesized for each candidate mRNA transcript, which transcript isobtained from the gene corresponding to the target polynucleotidesequence of interest. Once synthesized and quantitated, the oligomersare screened for efficiency of a transcript knock-out in a panel ofcancer cell lines. The efficiency of the knock-out is determined byanalyzing mRNA levels using lightcycler quantification. The oligomersthat resulted in the highest level of transcript knock-out, wherein thelevel was at least about 50%, preferably about 80-90%, up to 95% or moreup to undetectable message, are selected for use in a cell-basedproliferation assay, an anchorage independent growth assay, and anapoptosis assay.

The ability of each designed antisense oligonucleotide to inhibit geneexpression is tested through transfection into LNCaP, PC3, 22Rv1,MDA-PCA-2b, or DU145 prostate carcinoma cells. For each transfectionmixture, a carrier molecule (such as a lipid, lipid derivative,lipid-like molecule, cholesterol, cholesterol derivative, orcholesterol-like molecule) is prepared to a working concentration of 0.5mM in water, sonicated to yield a uniform solution, and filtered througha 0.45 μm PVDF membrane. The antisense or control oligonucleotide isthen prepared to a working concentration of 100 μM in sterile Milliporewater. The oligonucleotide is further diluted in OptiMEM™ (Gibco/BRL),in a microfuge tube, to 2 μM, or approximately 20 μg oligo/ml ofOptiMEM™. In a separate microfuge tube, the carrier molecule, typicallyin the amount of about 1.5-2 nmol carrier/μg antisense oligonucleotide,is diluted into the same volume of OptiMEM™ used to dilute theoligonucleotide. The diluted antisense oligonucleotide is immediatelyadded to the diluted carrier and mixed by pipetting up and down.Oligonucleotide is added to the cells to a final concentration of 30 nM.

The level of target mRNA that corresponds to a target gene of interestin the transfected cells is quantitated in the cancer cell lines usingthe Roche LightCycler™ real-time PCR machine. Values for the target mRNAare normalized versus an internal control (e.g., beta-actin). For each20 μl reaction, extracted RNA (generally 0.2-1 μg total) is placed intoa sterile 0.5 or 1.5 ml microcentrifuge tube, and water is added to atotal volume of 12.5 μl. To each tube is added 7.5 μl of a buffer/enzymemixture, prepared by mixing (in the order listed) 2.5 μl H₂O, 2.0 μl 10×reaction buffer, 10 μl oligo dT (20 pmol), 1.0 μl dNTP mix (10 mM each),0.5 μl RNAsin® (20 u) (Ambion, Inc., Hialeah, Fla.), and 0.5 μl MMLVreverse transcriptase (50 u) (Ambion, Inc.). The contents are mixed bypipetting up and down, and the reaction mixture is incubated at 42° C.for 1 hour. The contents of each tube are centrifuged prior toamplification.

An amplification mixture is prepared by mixing in the following order:1×PCR buffer II, 3 mM MgCl₂, 140 μM each dNTP, 0.175 pmol each oligo,1:50,000 dil of SYBR® Green, 0.25 mg/ml BSA, 1 unit Taq polymerase, andH₂O to 20 μl. (PCR buffer II is available in 10× concentration fromPerkin-Elmer, Norwalk, Conn.). In 1× concentration it contains 10 mMTris pH 8.3 and 50 mM KCl. SYBR® Green (Molecular Probes, Eugene, Oreg.)is a dye which fluoresces when bound to double stranded DNA. As doublestranded PCR product is produced during amplification, the fluorescencefrom SYBR® Green increases. To each 20 μl aliquot of amplificationmixture, 2 μl of template RT is added, and amplification is carried outaccording to standard protocols. The results are expressed as thepercent decrease in expression of the corresponding gene productrelative to non-transfected cells, vehicle-only transfected(mock-transfected) cells, or cells transfected with reverse controloligonucleotides.

Example 99 Effect of Expression on Proliferation

The effect of gene expression on the inhibition of cell proliferationcan be assessed in metastatic breast cancer cell lines (MDA-MB-231(“231”)); SW620 colon colorectal carcinoma cells; SKOV3 cells (a humanovarian carcinoma cell line); or LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145prostate cancer cells.

Cells are plated to approximately 60-80% confluency in 96-well dishes.Antisense or reverse control oligonucleotide is diluted to 2 μM inOptiMEM™. The oligonucleotide-OptiMEM™ can then be added to a deliveryvehicle, which delivery vehicle can be selected so as to be optimizedfor the particular cell type to be used in the assay. The oligo/deliveryvehicle mixture is then further diluted into medium with serum on thecells. The final concentration of oligonucleotide for all experimentscan be about 300 nM.

Antisense oligonucleotides are prepared as described above. Cells aretransfected overnight at 37° C. and the transfection mixture is replacedwith fresh medium the next morning. Transfection is carried out asdescribed above 8.

Those antisense oligonucleotides that result in inhibition ofproliferation of SW620 cells indicate that the corresponding gene playsa role in production or maintenance of the cancerous phenotype incancerous colon cells. Those antisense oligonucleotides that inhibitproliferation in SKOV3 cells represent genes that play a role inproduction or maintenance of the cancerous phenotype in cancerous breastcells. Those antisense oligonucleotides that result in inhibition ofproliferation of MDA-MB-231 cells indicate that the corresponding geneplays a role in production or maintenance of the cancerous phenotype incancerous ovarian cells. Those antisense oligonucleotides that inhibitproliferation in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells representgenes that play a role in production or maintenance of the cancerousphenotype in cancerous prostate cells.

Example 100 Effect of Gene Expression on Cell Migration

The effect of gene expression on the inhibition of cell migration can beassessed in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancercells using static endothelial cell binding assays, non-staticendothelial cell binding assays, and transmigration assays.

For the static endothelial cell binding assay, antisenseoligonucleotides are prepared as described above. Two days prior to use,prostate cancer cells (CaP) are plated and transfected with antisenseoligonucleotide as described above On the day before use, the medium isreplaced with fresh medium, and on the day of use, the medium isreplaced with fresh medium containing 2 μM CellTracker green CMFDA(Molecular Probes, Inc.) and cells are incubated for 30 min. Followingincubation, CaP medium is replaced with fresh medium (no CMFDA) andcells are incubated for an additional 30-60 min. CaP cells are detachedusing CMF PBS/2.5 mM EDTA or trypsin, spun and resuspended in DMEM/1%BSA/10 mM HEPES pH 7.0. Finally, CaP cells are counted and resuspendedat a concentration of 1×10⁶ cells/ml.

Endothelial cells (EC) are plated onto 96-well plates at 40-50%confluence 3 days prior to use. On the day of use, EC are washed 1× withPBS and 50) DMDM/1% BSA/10 mM HEPES pH 7 is added to each well. To eachwell is then added 50K (50λ) CaP cells in DMEM/1% BSA/10 mM HEPES pH 7.The plates are incubated for an additional 30 min and washed 5× with PBScontaining Ca⁺⁺ and Mg⁺⁺. After the final wash, 100 μL PBS is added toeach well and fluorescence is read on a fluorescent plate reader(Ab492/Em 516 nm).

For the non-static endothelial cell binding assay, CaP are prepared asdescribed above. EC are plated onto 24-well plates at 30-40% confluence3 days prior to use. On the day of use, a subset of EC are treated withcytokine for 6 hours then washed 2× with PBS. To each well is then added150-200K CaP cells in DMEM/1% BSA/10 mM HEPES pH 7. Plates are placed ona rotating shaker (70 RPM) for 30 min and then washed 3× with PBScontaining Ca⁺⁺ and Mg⁺⁺. After the final wash, 500 μL PBS is added toeach well and fluorescence is read on a fluorescent plate reader(Ab492/Em 516 nm).

For the transmigration assay, CaP are prepared as described above withthe following changes. On the day of use, CaP medium is replaced withfresh medium containing 5 μM CellTracker green CMFDA (Molecular Probes,Inc.) and cells are incubated for 30 min. Following incubation, CaPmedium is replaced with fresh medium (no CMFDA) and cells are incubatedfor an additional 30-60 min. CaP cells are detached using CMF PBS/2.5 mMEDTA or trypsin, spun and resuspended in EGM-2-MV medium. Finally, CaPcells are counted and resuspended at a concentration of 1×10⁶ cells/ml.

EC are plated onto FluorBlok transwells (BD Biosciences) at 30-40%confluence 5-7 days before use. Medium is replaced with fresh medium 3days before use and on the day of use. To each transwell is then added50K labeled CaP. 30 min prior to the first fluorescence reading, 10 μgof FITC-dextran (10K MW) is added to the EC plated filter. Fluorescenceis then read at multiple time points on a fluorescent plate reader(Ab492/Em 516 nm).

Those antisense oligonucleotides that result in inhibition of binding ofLNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells toendothelial cells indicate that the corresponding gene plays a role inthe production or maintenance of the cancerous phenotype in cancerousprostate cells. Those antisense oligonucleotides that result ininhibition of endothelial cell transmigration by LNCaP, PC3, 22Rv1,MDA-PCA-2b, or DU145 prostate cancer cells indicate that thecorresponding gene plays a role in the production or maintenance of thecancerous phenotype in cancerous prostate cells.

Example 101 Effect of Gene Expression on Colony Formation

The effect of gene expression upon colony formation of SW620 cells,SKOV3 cells, MD-MBA-231 cells, LNCaP cells, PC3 cells, 22Rv1 cells,MDA-PCA-2b cells, and DU145 cells can be tested in a soft agar assay.Soft agar assays are conducted by first establishing a bottom layer of 2ml of 0.6% agar in media plated fresh within a few hours of layering onthe cells. The cell layer is formed on the bottom layer by removingcells transfected as described above from plates using 9.05% trypsin andwashing twice in media. The cells are counted in a Coulter counter, andresuspended to 10⁶ per ml in media. 10 μl aliquots are placed with mediain 96-well plates (to check counting with WST1), or diluted further forthe soft agar assay. 2000 cells are plated in 800 μl 0.4% agar induplicate wells above 0.6% agar bottom layer. After the cell layer agarsolidifies, 2 ml of media is dribbled on top and antisense or reversecontrol oligo (produced as described above) is added without deliveryvehicles. Fresh media and oligos are added every 3-4 days. Colonies formin 10 days to 3 weeks. Fields of colonies are counted by eye. Wst-1metabolism values can be used to compensate for small differences instarting cell number. Larger fields can be scanned for visual record ofdifferences.

Those antisense oligonucleotides that result in inhibition of colonyformation of SW620 cells indicate that the corresponding gene plays arole in production or maintenance of the cancerous phenotype incancerous colon cells. Those antisense oligonucleotides that inhibitcolony formation in SKOV3 cells represent genes that play a role inproduction or maintenance of the cancerous phenotype in cancerous breastcells. Those antisense oligonucleotides that result in inhibition ofcolony formation of MDA-MB-231 cells indicate that the correspondinggene plays a role in production or maintenance of the cancerousphenotype in cancerous ovarian cells. Those antisense oligonucleotidesthat inhibit colony formation in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145cells represent genes that play a role in production or maintenance ofthe cancerous phenotype in cancerous prostate cells.

Example 102 Induction of Cell Death upon Depletion of Polypeptides byDepletion of mRNA (“Antisense Knockout”)

In order to assess the effect of depletion of a target message upon celldeath, LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells, or other cellsderived from a cancer of interest, can be transfected for proliferationassays. For cytotoxic effect in the presence of cisplatin (cis), thesame protocol is followed but cells are left in the presence of 2 μMdrug. Each day, cytotoxicity is monitored by measuring the amount of LDHenzyme released in the medium due to membrane damage. The activity ofLDH is measured using the Cytotoxicity Detection Kit from RocheMolecular Biochemicals. The data is provided as a ratio of LDH releasedin the medium vs. the total LDH present in the well at the same timepoint and treatment (rLDH/tLDH). A positive control using antisense andreverse control oligonucleotides for BCL2 (a known anti-apoptotic gene)is included; loss of message for BCL2 leads to an increase in cell deathcompared with treatment with the control oligonucleotide (backgroundcytotoxicity due to transfection).

Example 103 Functional Analysis of Gene Products DifferentiallyExpressed in Cancer

The gene products of sequences of a gene differentially expressed incancerous cells can be further analyzed to confirm the role and functionof the gene product in tumorigenesis, e.g., in promoting or inhibitingdevelopment of a metastatic phenotype. For example, the function of geneproducts corresponding to genes identified herein can be assessed byblocking function of the gene products in the cell. For example, wherethe gene product is secreted or associated with a cell surface membrane,blocking antibodies can be generated and added to cells to examine theeffect upon the cell phenotype in the context of, for example, thetransformation of the cell to a cancerous, particularly a metastatic,phenotype. In order to generate antibodies, a clone corresponding to aselected gene product is selected, and a sequence that represents apartial or complete coding sequence is obtained. The resulting clone isexpressed, the polypeptide produced isolated, and antibodies generated.The antibodies are then combined with cells and the effect upontumorigenesis assessed.

Where the gene product of the differentially expressed genes identifiedherein exhibits sequence homology to a protein of known function (e.g.,to a specific kinase or protease) and/or to a protein family of knownfunction (e.g., contains a domain or other consensus sequence present ina protease family or in a kinase family), then the role of the geneproduct in tumorigenesis, as well as the activity of the gene product,can be examined using small molecules that inhibit or enhance functionof the corresponding protein or protein family.

Additional functional assays include, but are not necessarily limitedto, those that analyze the effect of expression of the correspondinggene upon cell cycle and cell migration. Methods for performing suchassays are well known in the art.

Example 104 Deposit Information

A deposit of the biological materials in the tables referenced below wasmade with the American Type Culture Collection, 10801 University Blvd.,Manasas, Va. 20110-2209, under the provisions of the Budapest Treaty, onor before the filing date of the present application. The accessionnumber indicated is assigned after successful viability testing, and therequisite fees were paid. Access to said cultures will be availableduring pendency of the patent application to one determined by theCommissioner to be entitled to such under 37 C.F.R. §1.14 and 35 U.S.C.§122. All restriction on availability of said cultures to the publicwill be irrevocably removed upon the granting of a patent based upon theapplication. Moreover, the designated deposits will be maintained for aperiod of thirty (30) years from the date of deposit, or for five (5)years after the last request for the deposit; or for the enforceablelife of the U.S. patent, whichever is longer. Should a culture becomenonviable or be inadvertently destroyed, or, in the case ofplasmid-containing strains, lose its plasmid, it will be replaced with aviable culture(s) of the same taxonomic description.

These deposits are provided merely as a convenience to those of skill inthe art, and are not an admission that a deposit is required. A licensemay be required to make, use, or sell the deposited materials, and nosuch license is hereby granted. The deposit below was received by theATCC on or before the filing date of the present application. TABLE 155Cell Lines Deposited with ATCC ATCC CMCC Cell Line Deposit DateAccession No. Accession No. KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12CMay 15, 1998 CRL-12533 11611 MDA-MB- May 15, 1998 CRL-12532 10583 231MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containingspecific clones, were assigned an “ES” number (internal reference) anddeposited with the ATCC. Table 156 below provides the ATCC AccessionNos. of the clones deposited as a library named ES217. The deposit wasmade on Jan. 18, 2001. Table 157 (inserted before the claims) providesthe ATCC Accession Nos. of the clones deposited as libraries namedES210-ES216 on Jul. 25, 2000. TABLE 156 Clones Deposited as Library No.ES217 with ATCC on or before Jan. 18, 2001. CloneID CMCC# ATCC# CloneIDCMCC# ATCC# M00073094B:A01 5418 PTA-2918 M00073425A:H12 5418 PTA-2918M00073096B:A12 5418 PTA-2918 M00073427B:E04 5418 PTA-2918 M00073412C:E075418 PTA-2918 M00073408A:D06 5418 PTA-2918 M00073408C:F06 5418 PTA-2918M00073428D:H03 5418 PTA-2918 M00073435C:E06 5418 PTA-2918 M00073435B:E115418 PTA-2918 M00073403B:F06 5418 PTA-2918 M00074323D:F09 5418 PTA-2918M00073412D:B07 5418 PTA-2918 M00074333D:A11 5418 PTA-2918 M00073421C:B075418 PTA-2918 M00074335A:H08 5418 PTA-2918 M00073429B:H10 5418 PTA-2918M00074337A:G08 5418 PTA-2918 M00073412D:E02 5418 PTA-2918 M00074340B:D065418 PTA-2918 M00073097C:A03 5418 PTA-2918 M00074343C:A03 5418 PTA-2918M00073403C:C10 5418 PTA-2918 M00074346A:H09 5418 PTA-2918 M00073425D:F085418 PTA-2918 M00074347B:F11 5418 PTA-2918 M00073403C:E11 5418 PTA-2918M00074349A:E08 5418 PTA-2918 M00073431A:G02 5418 PTA-2918 M00074355D:H065418 PTA-2918 M00073412A:C03 5418 PTA-2918 M00074361C:B01 5418 PTA-2918M00073424D:C03 5418 PTA-2918 M00074365A:E09 5418 PTA-2918 M00073430C:A015418 PTA-2918 M00074366A:D07 5418 PTA-2918 M00073407A:E12 5418 PTA-2918M00074366A:H07 5418 PTA-2918 M00073412A:H09 5418 PTA-2918 M00074370D:G095418 PTA-2918 M00073418B:B09 5418 PTA-2918 M00074375D:E05 5418 PTA-2918M00073403C:H09 5418 PTA-2918 M00074382D:F04 5418 PTA-2918 M00073416B:F015418 PTA-2918 M00074384D:G07 5418 PTA-2918 M00073425A:G10 5418 PTA-2918M00074388B:E07 5418 PTA-2918 M00073427B:C08 5418 PTA-2918 M00074392C:D025418 PTA-2918 M00073430C:B02 5418 PTA-2918 M00074405B:A04 5418 PTA-2918M00073418B:H09 5418 PTA-2918 M00074417D:F07 5418 PTA-2918 M00073423C:E015418 PTA-2918 M00074392D:D01 5418 PTA-2918 M00074391B:D02 5418 PTA-2918M00074406B:F10 5418 PTA-2918 M00074390C:E04 5418 PTA-2918 M00074430D:G095418 PTA-2918 M00074411B:G07 5418 PTA-2918 M00074395A:B11 5418 PTA-2918M00074415B:A01 5418 PTA-2918 M00074404B:H01 5418 PTA-2918

TABLE 157 ES No. CLONE ID ATCC# ES 210 M00073054A:A06 PTA-2376 ES 210M00073054A:C10 PTA-2376 ES 210 M00073054B:E07 PTA-2376 ES 210M00073054C:E02 PTA-2376 ES 210 M00073055D:E11 PTA-2376 ES 210M00073056C:A09 PTA-2376 ES 210 M00073056C:C12 PTA-2376 ES 210M00073057A:F09 PTA-2376 ES 210 M00073057D:A12 PTA-2376 ES 210M00073060B:C06 PTA-2376 ES 210 M00073061B:F10 PTA-2376 ES 210M00073061C:G08 PTA-2376 ES 210 M00073062B:D09 PTA-2376 ES 210M00073062C:D09 PTA-2376 ES 210 M00073064C:A11 PTA-2376 ES 210M00073064C:H09 PTA-2376 ES 210 M00073064D:B11 PTA-2376 ES 210M00073065D:D11 PTA-2376 ES 210 M00073066B:G03 PTA-2376 ES 210M00073066C:D02 PTA-2376 ES 210 M00073067A:E09 PTA-2376 ES 210M00073067B:D04 PTA-2376 ES 210 M00073067D:B02 PTA-2376 ES 210M00073069D:G03 PTA-2376 ES 210 M00073070A:B12 PTA-2376 ES 210M00073070B:B06 PTA-2376 ES 210 M00073071D:D02 PTA-2376 ES 210M00073072A:A10 PTA-2376 ES 210 M00073074B:G04 PTA-2376 ES 210M00073074D:A04 PTA-2376 ES 210 M00073078B:F08 PTA-2376 ES 210M00073080B:A07 PTA-2376 ES 210 M00073081A:F08 PTA-2376 ES 210M00073081D:C07 PTA-2376 ES 210 M00073084C:E02 PTA-2376 ES 210M00073085D:B01 PTA-2376 ES 210 M00073086D:B05 PTA-2376 ES 210M00073088C:B04 PTA-2376 ES 210 M00073088D:F07 PTA-2376 ES 210M00073091B:C04 PTA-2376 ES 210 M00073091D:B06 PTA-2376 ES 210M00073092A:D03 PTA-2376 ES 210 M00073092D:B03 PTA-2376 ES 210M00073094B:A01 PTA-2376 ES 210 M00073412A:C03 PTA-2376 ES 210M00073408C:F06 PTA-2376 ES 210 M00073424D:C03 PTA-2376 ES 210M00073403B:F06 PTA-2376 ES 210 M00073407A:E12 PTA-2376 ES 210M00073412A:H09 PTA-2376 ES 210 M00073421C:B07 PTA-2376 ES 210M00073416B:F01 PTA-2376 ES 210 M00073425A:G10 PTA-2376 ES 210M00073425A:H12 PTA-2376 ES 210 M00073403C:C10 PTA-2376 ES 210M00073428D:H03 PTA-2376 ES 210 M00073403C:E11 PTA-2376 ES 210M00073435B:E11 PTA-2376 ES 210 M00073431A:G02 PTA-2376 ES 210M00073412C:E07 PTA-2376 ES 210 M00073435C:E06 PTA-2376 ES 210M00073412D:B07 PTA-2376 ES 210 M00073429B:H10 PTA-2376 ES 210M00073403C:H09 PTA-2376 ES 210 M00073412D:E02 PTA-2376 ES 210M00073427B:C08 PTA-2376 ES 210 M00073423C:E01 PTA-2376 ES 210M00073427B:E04 PTA-2376 ES 210 M00073425D:F08 PTA-2376 ES 210M00073096B:A12 PTA-2376 ES 210 M00073430C:A01 PTA-2376 ES 210M00073418B:B09 PTA-2376 ES 210 M00073430C:B02 PTA-2376 ES 210M00073097C:A03 PTA-2376 ES 210 M00073418B:H09 PTA-2376 ES 210M00073408A:D06 PTA-2376 ES 210 M00073438A:A08 PTA-2376 ES 210M00073438A:B02 PTA-2376 ES 210 M00073438D:G05 PTA-2376 ES 210M00073442A:F07 PTA-2376 ES 210 M00073442B:D12 PTA-2376 ES 210M00073442D:E11 PTA-2376 ES 210 M00073446C:A03 PTA-2376 ES 210M00073447B:A03 PTA-2376 ES 210 M00073447D:F01 PTA-2376 ES 210M00073448B:F11 PTA-2376 ES 210 M00073448B:F07 PTA-2376 ES 210M00073453C:C09 PTA-2376 ES 210 M00073455C:G09 PTA-2376 ES 210M00073457A:G09 PTA-2376 ES 210 M00073462C:H12 PTA-2376 ES 210M00073462D:D12 PTA-2376 ES 210 M00073464B:E01 PTA-2376 ES 210M00073464D:G12 PTA-2376 ES 210 M00073465A:H08 PTA-2376 ES 210M00073469B:A09 PTA-2376 ES 210 M00073469D:A06 PTA-2376 ES 210M00073470D:A01 PTA-2376 ES 210 M00073474A:G11 PTA-2376 ES 210M00073474C:F08 PTA-2376 ES 210 M00073475D:E05 PTA-2376 ES 210M00073478C:A07 PTA-2376 ES 210 M00073483B:C07 PTA-2376 ES 210M00073484B:A05 PTA-2376 ES 210 M00073484C:B04 PTA-2376 ES 210M00073486A:A12 PTA-2376 ES 210 M00073487A:C07 PTA-2376 ES 210M00073489B:A07 PTA-2376 ES 210 M00073493A:E12 PTA-2376 ES 210M00073493D:F05 PTA-2376 ES 210 M00073495B:G11 PTA-2376 ES 210M00073497C:D03 PTA-2376 ES 210 M00073504D:F03 PTA-2376 ES 210M00073505D:F01 PTA-2376 ES 210 M00073509B:B11 PTA-2376 ES 210M00073509B:E03 PTA-2376 ES 210 M00073513A:G07 PTA-2376 ES 210M00073513D:A11 PTA-2376 ES 210 M00073515A:F09 PTA-2376 ES 210M00073517A:A06 PTA-2376 ES 210 M00073517D:F11 PTA-2376 ES 210M00073520D:A04 PTA-2376 ES 210 M00073524A:A03 PTA-2376 ES 210M00073524A:G05 PTA-2376 ES 210 M00073529A:F03 PTA-2376 ES 210M00073530B:A02 PTA-2376 ES 210 M00073531B:H02 PTA-2376 ES 210M00073531C:F12 PTA-2376 ES 210 M00073537B:A12 PTA-2376 ES 210M00073539C:H05 PTA-2376 ES 210 M00073541B:C10 PTA-2376 ES 210M00073547B:F04 PTA-2376 ES 210 M00073547C:D02 PTA-2376 ES 210M00073549B:B03 PTA-2376 ES 210 M00073551B:E10 PTA-2376 ES 210M00073552A:F06 PTA-2376 ES 210 M00073554A:C01 PTA-2376 ES 210M00073554A:G04 PTA-2376 ES 210 M00073554B:A08 PTA-2376 ES 210M00073554B:D11 PTA-2376 ES 210 M00073555A:B09 PTA-2376 ES 210M00073555D:B04 PTA-2376 ES 210 M00073557A:A05 PTA-2376 ES 210M00073558A:A02 PTA-2376 ES 210 M00073561C:A04 PTA-2376 ES 210M00073565D:E05 PTA-2376 ES 210 M00073566A:G01 PTA-2376 ES 210M00073568A:G06 PTA-2376 ES 210 M00073568C:G07 PTA-2376 ES 210M00073569A:H02 PTA-2376 ES 210 M00073571A:F12 PTA-2376 ES 210M00073575B:H12 PTA-2376 ES 210 M00073576B:E03 PTA-2376 ES 210M00073576C:C11 PTA-2376 ES 210 M00073577B:D12 PTA-2376 ES 210M00073579B:A04 PTA-2376 ES 210 M00073580A:D08 PTA-2376 ES 210M00073587D:E12 PTA-2376 ES 210 M00073588B:H07 PTA-2376 ES 210M00073590C:F07 PTA-2376 ES 210 M00073592B:D09 PTA-2376 ES 210M00073594B:B11 PTA-2376 ES 210 M00073595D:A11 PTA-2376 ES 210M00073598D:E11 PTA-2376 ES 210 M00073599C:E08 PTA-2376 ES 210M00073601A:B06 PTA-2376 ES 210 M00073601A:F07 PTA-2376 ES 210M00073601D:D08 PTA-2376 ES 210 M00073603A:F04 PTA-2376 ES 210M00073603B:C03 PTA-2376 ES 210 M00073603C:A11 PTA-2376 ES 210M00073603C:C02 PTA-2376 ES 210 M00073603D:E07 PTA-2376 ES 210M00073604B:B07 PTA-2376 ES 210 M00073604B:H06 PTA-2376 ES 210M00073604C:H09 PTA-2376 ES 210 M00073605B:F10 PTA-2376 ES 210M00073605B:F11 PTA-2376 ES 210 M00073606D:F12 PTA-2376 ES 210M00073610A:F06 PTA-2376 ES 210 M00073614B:A12 PTA-2376 ES 210M00073614B:G09 PTA-2376 ES 210 M00073614C:F06 PTA-2376 ES 210M00073615D:E03 PTA-2376 ES 210 M00073616A:F06 PTA-2376 ES 210M00073617A:H04 PTA-2376 ES 210 M00073620A:G05 PTA-2376 ES 210M00073621D:A04 PTA-2376 ES 210 M00073621D:D02 PTA-2376 ES 210M00073621D:H05 PTA-2376 ES 210 M00073623D:H10 PTA-2376 ES 210M00073625C:D09 PTA-2376 ES 211 M00073626D:A01 PTA-2377 ES 211M00073628A:E03 PTA-2377 ES 211 M00073630A:C03 PTA-2377 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ES 216M00075228D:G09 PTA-2382 ES 216 M00075232C:A06 PTA-2382 ES 216M00075232D:C06 PTA-2382 ES 216 M00075234C:E06 PTA-2382 ES 216M00075239C:D06 PTA-2382 ES 216 M00075242A:G04 PTA-2382 ES 216M00075243D:F04 PTA-2382 ES 216 M00075245A:A06 PTA-2382 ES 216M00075249A:B08 PTA-2382 ES 216 M00075252B:F10 PTA-2382 ES 216M00075255A:G11 PTA-2382 ES 216 M00075259C:G02 PTA-2382 ES 216M00075270D:A02 PTA-2382 ES 216 M00075273C:E01 PTA-2382 ES 216M00075274B:F06 PTA-2382 ES 216 M00075275B:H07 PTA-2382 ES 216M00075279C:E08 PTA-2382 ES 216 M00075283A:F04 PTA-2382 ES 216M00075302B:C07 PTA-2382 ES 216 M00075305C:C07 PTA-2382 ES 216M00075309C:A06 PTA-2382 ES 216 M00075323B:B12 PTA-2382 ES 216M00075324B:C10 PTA-2382 ES 216 M00075324D:E02 PTA-2382 ES 216M00075326C:B01 PTA-2382 ES 216 M00075326D:A09 PTA-2382 ES 216M00075329B:E10 PTA-2382 ES 216 M00075330D:F11 PTA-2382 ES 216M00075333D:B07 PTA-2382 ES 216 M00075333D:D10 PTA-2382 ES 216M00075336B:B04 PTA-2382 ES 216 M00075344D:A08 PTA-2382 ES 216M00075347D:D01 PTA-2382 ES 216 M00075354A:D11 PTA-2382 ES 216M00075354A:G12 PTA-2382 ES 216 M00075354C:B12 PTA-2382 ES 216M00075360D:D04 PTA-2382 ES 216 M00075365B:B06 PTA-2382 ES 216M00075384A:B03 PTA-2382 ES 216 M00075389B:C06 PTA-2382 ES 216M00075391D:D07 PTA-2382 ES 216 M00075402A:F01 PTA-2382 ES 216M00075405B:C07 PTA-2382 ES 216 M00075405D:A10 PTA-2382 ES 216M00075365D:B08 PTA-2382 ES 216 M00075380D:F06 PTA-2382 ES 216M00075356D:C03 PTA-2382 ES 216 M00075352D:F09 PTA-2382 ES 216M00075359D:E09 PTA-2382 ES 216 M00075365D:H01 PTA-2382 ES 216M00075373C:B09 PTA-2382 ES 216 M00075378B:C07 PTA-2382 ES 216M00075379A:E07 PTA-2382 ES 216 M00075383A:B11 PTA-2382 ES 216M00075407A:B05 PTA-2382 ES 216 M00075409A:E04 PTA-2382 ES 216M00075409B:G12 PTA-2382 ES 216 M00075416C:B02 PTA-2382 ES 216M00075458B:F09 PTA-2382 ES 216 M00075464C:A07 PTA-2382 ES 216M00075458C:F01 PTA-2382 ES 216 M00075463C:E07 PTA-2382 ES 216M00075464C:C04 PTA-2382 ES 216 M00075448B:G11 PTA-2382 ES 216M00075434A:D06 PTA-2382 ES 216 M00075457C:A06 PTA-2382 ES 216M00075454C:D06 PTA-2382 ES 216 M00075460C:B06 PTA-2382 ES 216M00075459A:C02 PTA-2382 ES 216 M00075414A:D10 PTA-2382 ES 216M00075433A:C06 PTA-2382 ES 216 M00075505B:A04 PTA-2382 ES 216M00075474D:B07 PTA-2382 ES 216 M00075504B:A10 PTA-2382 ES 216M00075473C:E08 PTA-2382 ES 216 M00075499A:H02 PTA-2382 ES 216M00075495D:D11 PTA-2382 ES 216 M00075496D:G05 PTA-2382 ES 216M00075514A:G12 PTA-2382 ES 216 M00075495B:C12 PTA-2382 ES 216M00075497D:H03 PTA-2382 ES 216 M00075529A:A02 PTA-2382 ES 216M00075538C:E03 PTA-2382 ES 216 M00075544A:C03 PTA-2382 ES 216M00075598B:A09 PTA-2382 ES 216 M00075521B:E11 PTA-2382 ES 216M00075597C:G01 PTA-2382 ES 216 M00075584D:B05 PTA-2382 ES 216M00075590B:G04 PTA-2382 ES 216 M00075603D:D09 PTA-2382 ES 216M00075607B:D05 PTA-2382 ES 216 M00075609A:H06 PTA-2382 ES 216M00075613D:F01 PTA-2382 ES 216 M00075619C:D08 PTA-2382 ES 216M00075621A:F06 PTA-2382 ES 216 M00075639A:D12 PTA-2382

Retrieval of Individual Clones from Deposit of Pooled Clones. Where theATCC deposit is composed of a pool of cDNA clones or a library of cDNAclones, the deposit was prepared by first transfecting each of theclones into separate bacterial cells. The clones in the pool or librarywere then deposited as a pool of equal mixtures in the compositedeposit. Particular clones can be obtained from the composite depositusing methods well known in the art. For example, a bacterial cellcontaining a particular clone can be identified by isolating singlecolonies, and identifying colonies containing the specific clone throughstandard colony hybridization techniques, using an oligonucleotide probeor probes designed to specifically hybridize to a sequence of the cloneinsert (e.g., a probe based upon unmasked sequence of the encodedpolynucleotide having the indicated SEQ ID NO). The probe should bedesigned to have a T_(m) of approximately 80° C. (assuming 2° C. foreach A or T and 4° C. for each G or C). Positive colonies can then bepicked, grown in culture, and the recombinant clone isolated.Alternatively, probes designed in this manner can be used to PCR toisolate a nucleic acid molecule from the pooled clones according tomethods well known in the art, e.g., by purifying the cDNA from thedeposited culture pool, and using the probes in PCR reactions to producean amplified product having the corresponding desired polynucleotidesequence.

Example 105 Detection of Genes that are Differentially Expressed inCancer Cells

Polynucleotides for use on the arrays were obtained from both publiclyavailable sources and from cDNA libraries generated from selected celllines and patient tissues. Table 158 (inserted prior to claims) providesinformation about the polynucleotides on the arrays including: (a) the“SEQ ID”, corresponding to the sequences of the Sequence Listingprovided herein; (b) the “SeqName”, corresponding to a internalreference name for the sequence; (c) the “Clone Id”, corresponding tothe identifier of a clone from which the sequence is derived; (d) the“Seq Type”, corresponding to the type of the sequence, either interenalor consensus; (e) the “Lib. Name”, corresponding to the library fromwhich the clone was obtained; (f) the “Cluster Id”, corresponding to aninternal identifier for a set of sequences that have been grouped, i.e.,clustered, based on their sequence identity, and (g), the “Length”,corresponding to the length of the sequence.

Normal and cancerous tissues were collected from patients using lasercapture microdissection (LCM) techniques, which techniques are wellknown in the art (see, e.g., Ohyama et al. (2000) Biotechniques29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al.(1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Bucket al. (1996) Science 274:998-1001).

In general, patients (pats) had breast cancer (brst), prostate cancer(prst), colon cancer (cln). Patients with colon cancer had metastasizedcolon cancer (met or M), and/or primary tumors (T). Metastases of coloncancers may appear in any tissue, including bone, breast, lung, liver,brain, kidney skin, intestine, appendix, etc. In many patients, thecolon cancer had metastasized to liver.

cDNA probes were prepared from total RNA isolated from the patientsamples described above. Since LCM provides for the isolation ofspecific cell types to provide a substantially homogenous cell sample,this provided for a similarly pure RNA sample.

In most experiments, total RNA was first reverse transcribed into cDNAusing a primer containing a T7 RNA polymerase promoter, followed bysecond strand DNA synthesis. cDNA was then transcribed in vitro toproduce antisense RNA using the T7 promoter-mediated expression (see,e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA wasthen converted into cDNA. The second set of cDNAs were again transcribedin vitro, using the T7 promoter, to provide antisense RNA. Optionally,the RNA was again converted into cDNA, allowing for up to a third roundof T7-mediated amplification to produce more antisense RNA. Thus theprocedure provided for two or three rounds of in vitro transcription toproduce the final RNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to theantisense RNA mix, and producing fluorescently labeled cDNA from the RNAstarting material. Fluorescently labeled cDNAs prepared from the tumorRNA sample were compared to fluorescently labeled cDNAs prepared from anormal cell RNA sample. For example, the cDNA probes from the normalcells were labeled with Cy3 fluorescent dye (green) and the cDNA probesprepared from the tumor cells were labeled with Cy5 fluorescent dye(red), and vice versa.

In many experiments, each array used had an identical spatial layout andcontrol spot set. Each microarray was divided into two areas, each areahaving an array with, on each half, twelve groupings of 32×12 spots, fora total of about 9,216 spots on each array. The two areas are spottedidentically which provides for at least two duplicates of each clone perarray.

Polynucleotides for use on the arrays were obtained from both publiclyavailable sources and from cDNA libraries generated from selected celllines and patient tissues as described. PCR products of from about 0.5kb to 2.0 kb amplified from these sources were spotted onto the arrayusing a Molecular Dynamics Gen III spotter according to themanufacturer's recommendations. The first row of each of the 24 regionson the array had about 32 control spots, including 4 negative controlspots and 8 test polynucleotides. The test polynucleotides were spikedinto each sample before the labeling reaction with a range ofconcentrations from 2-600 pg/slide and ratios of 1:1. For each arraydesign, two slides were hybridized with the test samples reverse-labeledin the labeling reaction. This provided for about four duplicatemeasurements for each clone, two of one color and two of the other, foreach sample. In some experiments Affymetrix oligonucleotide arrays wereused.

The differential expression assay was performed by mixing equal amountsof probes from matched or unmatched samples. The arrays werepre-incubated for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, andthen washed three times in water and twice in isopropanol. Followingprehybridization of the array, the probe mixture was then hybridized tothe array under conditions of high stringency (overnight at 42° C. in50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array waswashed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2%SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using aMolecular Dynamics Generation III dual color laser-scanner/detector. Theimages were processed using BioDiscovery Autogene software, and the datafrom each scan set normalized to provide for a ratio of expressionrelative to normal.

The experiment was repeated, this time labeling the two probes with theopposite color in order to perform the assay in both “color directions.”Each experiment was sometimes repeated with two more slides (one in eachcolor direction). The level of fluorescence for each sequence on thearray expressed as a ratio of the geometric mean of 8 replicatespots/genes from the four arrays or 4 replicate spots/gene from 2 arraysor some other permutation. The data were normalized using the spikedpositive controls present in each duplicated area, and the precision ofthis normalization was included in the final determination of thesignificance of each differential. The fluorescent intensity of eachspot was also compared to the negative controls in each duplicated areato determine which spots have detected significant expression levels ineach sample.

A statistical analysis of the fluorescent intensities was applied toeach set of duplicate spots to assess the precision and significance ofeach differential measurement, resulting in a p-value testing the nullhypothesis that there is no differential in the expression level betweenthe tumor and normal samples of each patient. During initial analysis ofthe microarrays, the hypothesis was accepted if p>10⁻³, and thedifferential ratio was set to 1.000 for those spots. All other spotshave a significant difference in expression between the matched orunmatched samples. If the tumor sample has detectable expression and thenormal does not, the ratio is truncated at 1000 since the value forexpression in the normal sample would be zero, and the ratio would notbe a mathematically useful value (e.g., infinity). If the normal samplehas detectable expression and the tumor does not, the ratio is truncatedto 0.001, since the value for expression in the tumor sample would bezero and the ratio would not be a mathematically useful value. Theselatter two situations are referred to herein as “on/off.” Databasetables were populated using a 95% confidence level (p>0.05).

Results

Table 159 provides results obtained according to the methods set forthabove. The results show data from several separate experiments using thesame set of gene products, each identified by SEQ ID NO. The results fora particular SEQ ID are expressed as a percentage of the total number ofpatients in which that SEQ ID was over-expressed by at least two fold ata 95% confidence level. Accordingly, for example, SEQ ID NO:23576, thefirst entry, is expressed in tumor samples of 21.74% (% Brst Pats) of 23patients (# Brst Pats) with breast cancer.

The six experiments were: 1) a comparison of the gene expression profileof cancerous breast cells to that of normal breast cells (results shownin column 3, entitled “% Brst Pats”), 2) a comparison of the geneexpression profile of cancerous colon cells (primary tumor) to that ofnormal colon cells (results shown in column 5, entitled “% Cln Pats”),3) a comparison of the gene expression profile of cancerous prostatecells to that of normal prostate cells (results shown in column 7,entitled “% Prst Pats”), 4) a comparison of the gene expression profileof metastasized cancerous colon cells to that of unmatched controls(i.e., a pooled sample of normal colon from many patients; results shownin column 9, entitled “% Cln Unm Met”), 5) a comparison of the geneexpression profile of cancerous metastasized colon cells to that ofmatched (i.e. from the same patient) normal colon cells (results shownin column 11, entitled “% Cln Match met”), and 6) a comparison of thegene expression profile of cancerous metastasized colon cells to that ofmatched (i.e., from the same patient) colon cancer cells from a primarytumor (results shown in column 13, entitled “% Cln Match Met M/T”). Alsoshown in Table 159 are “SPOT ID” entries, which correspond to aninternal reference identifier.

Table 160 also provides results obtained according to the methods setforth above. The results show data from several separate experimentsusing the same set of gene products, each identified by SEQ ID NO.Again, the results for a particular SEQ ID are expressed as a percentageof the total number of patients in which that SEQ ID was over-expressedby at least two fold at a 95% confidence level. Accordingly, forexample, SEQ ID NO:23569, the first entry, is expressed in breast tumorsamples of 24.44% (% Breast T/N>=2×) of 45 patients Breast T/N patients)with breast cancer.

The two experiments were: 1) a comparison of the gene expression profileof cancerous breast cells (primary tumor) to that of normal breast cells(results shown in column 3, entitled “% Breast T/N>=2×”), and 2) acomparison of the gene expression profile of cancerous colon cells(primary tumor) to that of normal colon cells (results shown in column5, entitled “% Colon T/N>=2×”). The number of patients in the patientsamples are shown in columns 4 and 6. Also known is a column entitled“PROBESET Id”, which corresponds to an internal reference identifier.

These data show that the sequences set forth in the in the sequencelisting may be used to detect cancerous cells, particularly, cancerouscolon, prostate, breast, and metastasized colon cells. TABLE 158 Seq IdSeqName Clone Id Seq Type Lib Name Cluster Id Length 235695059.K19.GZ43_643335 M00079817D:G03 internal chiron(27) 800071 519 235705060.E21.GZ43_643745 M00079848A:B09 internal chiron(27) 1089548 53523571 5060.G17.GZ43_643683 M00079856A:C12 internal chiron(27) 381805 44523572 5061.A19.gz43_646815 M00079888C:C02 internal chiron(27) 657028 61923573 5061.C02.gz43_646545 M00079891C:A07 internal chiron(27) 1117586637 23574 5061.E17.gz43_646787 M00079902A:G08 internal chiron(27)1116829 499 23575 5061.M03.gz43_646571 M00079929D:E09 internalchiron(27) 800071 557 23576 5061.N15.gz43_646764 M00079935C:A07 internalchiron(27) 398438 484 23577 5061.O18.gz43_646813 M00079939B:G07 internalchiron(27) 774843 635 23578 5061.P08.gz43_646654 M00079940C:D02 internalchiron(27) 431141 593 23579 5062.M21.GZ43_647243 M00079986C:G03 internalchiron(27) 42008 541 23580 5063.A16.GZ43_647535 M00079998A:H03 internalchiron(27) 42008 405 23581 5063.E24.GZ43_647667 M00080010A:G05 internalchiron(27) 583076 518 23582 5065.G16.GZ43_648309 M00080110D:D02 internalchiron(27) 1118029 590 23583 5065.P08.GZ43_648190 M00080136D:A10internal chiron(27) 807607 274 23584 5184.G17.GZ43_667153 M00082049D:B06internal chiron(28) 833900 472 23585 5185.K01.GZ43_667285 M00082099D:D04internal chiron(28) 149149 376 23586 5185.L02.GZ43_667302 M00082103C:H08internal chiron(28) 416674 329 23587 5185.L12.GZ43_667462 M00082104C:A10internal chiron(28) 158514 385 23588 5186.J19.GZ43_667956 M00082152A:B06internal chiron(29) 20806 562 23589 5186.J24.GZ43_668036 M00082152B:H01internal chiron(29) 1110239 556 23590 5186.N17.GZ43_667928M00082164D:A10 internal chiron(29) 410674 476 23591 5188.A08.GZ43_668539M00082232D:E02 internal chiron(29) 1118027 546 235925188.G06.GZ43_668513 M00082256A:E06 internal chiron(29) 551209 610 235935188.H20.GZ43_668738 M00082263A:F11 internal chiron(29) 525660 636 235945189.O12.GZ43_669001 M00082342A:A11 internal chiron(29) 480233 606 235955189.P10.GZ43_668970 M00082338A:C01 internal chiron(29) 726873 441 235965190.E23.GZ43_669551 M00082382D:C05 internal chiron(29) 1067312 62223597 5190.N13.GZ43_669400 M00082417A:E03 internal chiron(29) 410674 56323598 5191.G05.GZ43_669649 M00082457B:B05 internal chiron(29) 25422 49723599 5193.E14.GZ43_670943 M00082591A:A11 internal chiron(29) 967199 50123600 5193.M09.GZ43_670871 M00082618A:G07 internal chiron(29) 1135172662 23601 5193.O06.GZ43_670825 M00082628B:F05 internal chiron(29) 17174524 23602 5195.C15.GZ43_671725 M00082718D:E03 internal chiron(29) 400889613 23603 5195.E15.GZ43_671727 M00082729C:C08 internal chiron(29)1193184 602 23604 5234.B09.GZ43_673764 M00083298C:G12 internalchiron(29) 1119238 497 23605 5234.H23.GZ43_673994 M00083332C:D11internal chiron(29) 25422 644 23606 5234.O05.GZ43_673713 M00083289D:G08internal chiron(29) 583076 624 23607 5236.J03.GZ43_674444 M00083437D:E04internal chiron(29) 606382 426 23608 5236.O18.GZ43_674689 M00083459D:B01internal chiron(29) 378206 580 23609 5238.A24.GZ43_675194 M00083524A:G10internal chiron(29) 726873 473 23610 Clu1052434.con_1 consensus 1052434352 23611 Clu1052615.con_1 consensus 1052615 439 23612 Clu1053096.con_1consensus 1053096 529 23613 Clu1058283.con_1 consensus 1058283 824 23614Clu1067312.con_1 consensus 1067312 691 23615 Clu1069553.con_2 consensus1069553 576 23616 Clu1080217.con_1 consensus 1080217 547 23617Clu1081611.con_1 consensus 1081611 399 23618 Clu1082099.con_1 consensus1082099 440 23619 Clu1082189.con_1 consensus 1082189 470 23620Clu1082283.con_2 consensus 1082283 529 23621 Clu1082399.con_1 consensus1082399 534 23622 Clu1082489.con_1 consensus 1082489 355 23623Clu1082628.con_1 consensus 1082628 554 23624 Clu1082731.con_1 consensus1082731 289 23625 Clu1083148.con_1 consensus 1083148 757 23626Clu1083900.con_1 consensus 1083900 502 23627 Clu1089548.con_1 consensus1089548 667 23628 Clu1116089.con_1 consensus 1116089 369 23629Clu1116829.con_1 consensus 1116829 586 23630 Clu1116919.con_1 consensus1116919 806 23631 Clu1116945.con_1 consensus 1116945 566 23632Clu1117021.con_1 consensus 1117021 978 23633 Clu1117079.con_1 consensus1117079 543 23634 Clu1117586.con_1 consensus 1117586 678 23635Clu1117625.con_1 consensus 1117625 277 23636 Clu1118027.con_1 consensus1118027 590 23637 Clu1118511.con_1 consensus 1118511 815 23638Clu1119238.con_1 consensus 1119238 588 23639 Clu1119896.con_1 consensus1119896 386 23640 Clu1126645.con_1 consensus 1126645 509 23641Clu1132147.con_1 consensus 1132147 583 23642 Clu1139444.con_1 consensus1139444 677 23643 Clu1139499.con_1 consensus 1139499 498 23644Clu1140276.con_1 consensus 1140276 485 23645 Clu1140367.con_2 consensus1140367 424 23646 Clu1140589.con_1 consensus 1140589 821 23647Clu1141931.con_1 consensus 1141931 565 23648 Clu1193580.con_1 consensus1193580 629 23649 Clu1193799.con_1 consensus 1193799 733 23650Clu1193833.con_2 consensus 1193833 566 23651 Clu149149.con_2 consensus149149 564 23652 Clu19522.con_1 consensus 19522 809 23653 Clu21222.con_1consensus 21222 774 23654 Clu25422.con_1 consensus 25422 766 23655Clu258716.con_1 consensus 258716 872 23656 Clu374843.con_1 consensus374843 656 23657 Clu377719.con_1 consensus 377719 1382 23658Clu377939.con_1 consensus 377939 1152 23659 Clu378206.con_1 consensus378206 584 23660 Clu398438.con_1 consensus 398438 736 23661Clu400889.con_1 consensus 400889 741 23662 Clu403038.con_1 consensus403038 773 23663 Clu410674.con_1 consensus 410674 822 23664Clu411226.con_1 consensus 411226 907 23665 Clu413700.con_1 consensus413700 951 23666 Clu416674.con_1 consensus 416674 766 23667Clu42008.con_1 consensus 42008 1057 23668 Clu451094.con_1 consensus451094 443 23669 Clu451310.con_1 consensus 451310 484 23670Clu451496.con_2 consensus 451496 1000 23671 Clu455524.con_1 consensus455524 363 23672 Clu456861.con_1 consensus 456861 525 23673Clu480233.con_2 consensus 480233 622 23674 Clu512287.con_2 consensus512287 491 23675 Clu525660.con_1 consensus 525660 650 23676Clu532281.con_1 consensus 532281 636 23677 Clu552745.con_1 consensus552745 373 23678 Clu554732.con_1 consensus 554732 474 23679Clu556189.con_1 consensus 556189 698 23680 Clu579754.con_1 consensus579754 653 23681 Clu593641.con_1 consensus 593641 890 23682Clu643318.con_1 consensus 643318 498 23683 Clu657028.con_1 consensus657028 807 23684 5072.K10.GZ43_650909 M00080470D:C10 internal chiron(27)410674 557 23685 5072.P20.GZ43_651074 M00080489D:G10 internal chiron(27)856078 489 23686 5073.C07.GZ43_651237 M00080495C:B05 internal chiron(27)533096 590 23687 5073.D08.GZ43_651254 M00080498D:E12 internal chiron(27)1067312 578 23688 5073.J20.GZ43_651452 M00080515D:H06 internalchiron(27) 400889 504 23689 5074.H06.GZ43_651610 M00080558A:G02 internalchiron(27) 618862 544 23690 5074.J21.GZ43_651852 M00080569D:E04 internalchiron(27) 1118511 573 23691 5075.A20.GZ43_652211 M00080608C:E03internal chiron(27) 1117586 584 23692 5075.M03.GZ43_651951M00080642C:G04 internal chiron(27) 723800 577 23693 5076.B04.GZ43_652340M00080658D:B05 internal chiron(27) 1083148 615 236945076.H07.GZ43_652394 M00080683A:F07 internal chiron(27) 168428 548 236955076.P22.GZ43_652642 M00080721A:B11 internal chiron(27) 1118511 62523696 5097.D01.GZ43_652699 M00080728C:A06 internal chiron(27) 1116829533 23697 5097.M04.GZ43_652756 M00080734D:A04 internal chiron(27) 613936565 23698 5097.P10.GZ43_652855 M00080747A:B06 internal chiron(27) 831704195 23699 5098.C09.GZ43_653210 M00080839A:C05 internal chiron(27)1117079 536 23700 5098.E12.GZ43_653260 M00080849C:A06 internalchiron(27) 666002 500 23701 5130.F02.GZ43_659697 M00081454C:B02 internalchiron(28) 833900 670 23702 5130.O17.GZ43_659946 M00081478A:A12 internalchiron(28) 520284 542 23703 5130.P09.GZ43_659819 M00081479D:H03 internalchiron(28) 1138736 621 23704 5131.N24.GZ43_660441 M00081516A:F04internal chiron(28) 469630 455 23705 5132.D09.GZ43_660575 M00081524D:E12internal chiron(28) 411226 558 23706 5133.B13.GZ43_661021 M00081558D:C08internal chiron(28) 532281 415 23707 5133.G11.GZ43_660994 M00081568D:D02internal chiron(28) 89239 557 23708 5133.J24.GZ43_661205 M00081574B:A04internal chiron(28) 644751 550 23709 5133.N07.GZ43_660937 M00081580D:E03internal chiron(28) 526675 603 23710 5134.J13.GZ43_661413 M00081607C:D05internal chiron(28) 964646 489 23711 5134.N11.GZ43_661385 M00081616B:H01internal chiron(28) 454662 397 23712 5134.O05.GZ43_661290 M00081618A:B06internal chiron(28) 31223 491 23713 5136.B15.GZ43_662228 M00081661D:A10internal chiron(28) 1069553 413 23714 5136.H18.GZ43_662282M00081678A:A12 internal chiron(28) 512287 487 23715 5136.K03.GZ43_662045M00081683B:C09 internal chiron(28) 532281 626 23716 5136.K16.GZ43_662253M00081684B:C10 internal chiron(28) 378206 509 23717 5136.P01.GZ43_662018M00081693B:F12 internal chiron(28) 89239 495 23718 Clu666002.con_1consensus 666002 530 23719 Clu685022.con_1 consensus 685022 599 23720Clu715440.con_2 consensus 715440 611 23721 Clu726873.con_1 consensus726873 687 23722 Clu775364.con_1 consensus 775364 601 23723Clu800071.con_1 consensus 800071 685 23724 Clu807607.con_1 consensus807607 562 23725 Clu954632.con_1 consensus 954632 292 23726Clu964646.con_1 consensus 964646 526 23727 Clu982132.con_1 consensus982132 987 23728 5066.J20.GZ43_648760 M00080164D:H10 internal chiron(27)618862 344 23729 5066.N15.GZ43_648684 M00080179D:G07 internal chiron(27)1083148 259 23730 5066.O24.GZ43_648829 M00080184B:C10 internalchiron(27) 19522 303 23731 5069.A20.GZ43_649907 M00080285A:E12 internalchiron(27) 1119238 588 23732 5069.I09.GZ43_649739 M00080317A:G01internal chiron(27) 1117079 537 23733 5069.M04.GZ43_649663M00080331C:D09 internal chiron(27) 685022 592 23734 5070.G07.GZ43_650089M00080362D:F11 internal chiron(27) 258716 520 23735 5071.H06.GZ43_650458M00080407D:G09 internal chiron(27) 386188 216 23736 5071.J11.GZ43_650540M00080413D:D07 internal chiron(27) 1117021 569 237375098.I02.GZ43_653104 M00080819B:G07 internal chiron(27) 398438 459 237385101.B10.GZ43_654377 M00081030A:D09 internal chiron(28) 1139444 56223739 5102.A22.GZ43_654952 M00081093B:C04 internal chiron(28) 1139037467 23740 5103.J01.GZ43_655009 M00081178D:C12 internal chiron(28) 643318455 23741 5104.I13.GZ43_655584 M00081223D:D06 internal chiron(28) 558521637 23742 5104.O16.GZ43_655638 M00081228B:C04 internal chiron(28)1139048 327 23743 5105.P13.GZ43_655975 M00081288D:G08 internalchiron(28) 1140612 542 23744 5106.I21.GZ43_656480 M00081313D:B12internal chiron(28) 643318 498 23745 5106.M18.GZ43_656436 M00081323D:C07internal chiron(28) 964646 429 23746 5127.A11.GZ43_658684 M00081333C:A04internal chiron(28) 89239 438 23747 5127.E23.GZ43_658880 M00081344A:C10internal chiron(28) 715440 610 23748 5128.J24.GZ43_659285 M00081385B:D11internal chiron(28) 848070 546 23749 5128.L10.GZ43_659063 M00081388B:A12internal chiron(28) 1138291 483 23750 5129.J16.GZ43_659541M00081428A:B10 internal chiron(28) 1141931 482 237515129.P04.GZ43_659355 M00081441D:F01 internal chiron(28) 1117586 49623752 5130.C16.GZ43_659918 M00081450C:E09 internal chiron(28) 523988 57323753 5130.D14.GZ43_659887 M00081452A:G03 internal chiron(28) 631472 40823754 5177.B11.GZ43_664364 M00081717D:A10 internal chiron(28) 411226 36623755 5177.D13.GZ43_664398 M00081723A:C02 internal chiron(28) 1139444493 23756 5177.H05.GZ43_664274 M00081705D:B04 internal chiron(28) 964646406 23757 5178.G24.GZ43_664961 M00081767C:G04 internal chiron(28) 374843614 23758 5178.N01.GZ43_664600 M00081780B:F07 internal chiron(28) 884215516 23759 5179.I06.GZ43_665059 M00081806D:C10 internal chiron(28) 685022593 23760 5179.L07.GZ43_665078 M00081812D:A11 internal chiron(28) 9087444 23761 5181.B17.GZ43_665996 M00081873D:A03 internal chiron(28)1117625 129 23762 5181.C18.GZ43_666013 M00081878B:G04 internalchiron(28) 512287 434 23763 5181.O23.GZ43_666105 M00081914C:H06 internalchiron(28) 1140589 509 23764 5182.L02.GZ43_666150 M00081924D:E02internal chiron(28) 532281 627 23765 5182.M10.GZ43_666279 M00081938B:D03internal chiron(28) 480233 618 23766 5183.J06.GZ43_666596 M00081995C:C03internal chiron(28) 867272 521 23767 5183.K20.GZ43_666821 M00081999D:H07internal chiron(28) 416674 394

TABLE 159 # Cln # Cln # % Cln Unm % Cln Match % Cln % Cln SPOT % BrstBrst % Cln # Cln % Prst # Prst Unm Met Match Met M/N Match Match SEQ IDID Pats Pats Pats Pats Pats Pats Met Pats Met Pats Met M/T Met M/T 2357662615 21.74 23 15.79 19 97 5.56 18 5.56 18 23576 62615 21.74 23 15.79 1997 5.56 18 5.56 18 23577 42089 13.04 23 23.68 76 9.80 102 3.03 33 8.3336 36 23579 10592 23 24.68 77 102 12.12 33 16.67 36 36 23579 10592 2324.68 77 102 12.12 33 16.67 36 36 23580 10592 23 24.68 77 102 12.12 3316.67 36 36 23581 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 2323584 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23585 6223330.43 23 31.58 19 7.22 97 16.67 18 5.56 18 23585 53177 30.43 23 20.00 757.84 102 30.30 33 28.57 35 5.56 36 23585 62233 30.43 23 31.58 19 7.22 9716.67 18 5.56 18 23586 61035 17.39 23 15.79 19 22.68 97 5.56 18 18 2358661035 17.39 23 15.79 19 22.68 97 5.56 18 18 23588 65344 21.74 23 31.5819 97 16.67 18 18 23588 65344 21.74 23 31.58 19 97 16.67 18 18 2358865344 21.74 23 31.58 19 97 16.67 18 18 23588 61198 21.74 23 10.53 192.06 97 11.11 18 18 23588 61198 21.74 23 10.53 19 2.06 97 11.11 18 1823594 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23594 244038.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23596 62019 30.43 23 1997 18 18 23596 62019 30.43 23 19 97 18 18 23598 61000 26.09 23 5.26 1932.99 97 18 16.67 18 23598 61000 26.09 23 5.26 19 32.99 97 18 16.67 1823599 3835 8 20.00 35 2.94 34 23.33 30 14.29 7 7 23601 3835 8 20.00 352.94 34 23.33 30 14.29 7 7 23602 35056 4.35 23 30.67 75 1.96 102 54.5533 36.11 36 36 23603 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 2323 23603 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 2360561000 26.09 23 5.26 19 32.99 97 18 16.67 18 23605 61000 26.09 23 5.26 1932.99 97 18 16.67 18 23605 61000 26.09 23 5.26 19 32.99 97 18 16.67 1823605 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23606 24511 23 9.38 644.00 100 24.24 33 26.09 23 4.35 23 23607 65474 21.74 23 78.95 19 12.3797 66.67 18 18 23607 65474 21.74 23 78.95 19 12.37 97 66.67 18 18 2361462019 30.43 23 19 97 18 18 23614 62019 30.43 23 19 97 18 18 23615 5104226.09 23 2.67 75 3.92 102 3.03 33 35 36 23615 51042 26.09 23 2.67 753.92 102 3.03 33 35 36 23630 37575 4.35 23 22.67 75 14.71 102 33 36.1136 5.56 36 23630 37575 4.35 23 22.67 75 14.71 102 33 36.11 36 5.56 3623646 1542 8 54.29 35 20.59 34 40.00 30 57.14 7 7 23646 1542 8 54.29 3520.59 34 40.00 30 57.14 7 7 23646 46009 23 30.26 76 8.82 102 21.21 3351.43 35 5.56 36 23646 4066 8 28.57 35 11.76 34 26.67 30 42.86 7 7 236464066 8 28.57 35 11.76 34 26.67 30 42.86 7 7 23646 1542 8 54.29 35 20.5934 40.00 30 57.14 7 7 23651 53177 30.43 23 20.00 75 7.84 102 30.30 3328.57 35 5.56 36 23651 62233 30.43 23 31.58 19 7.22 97 16.67 18 5.56 1823651 62233 30.43 23 31.58 19 7.22 97 16.67 18 5.56 18 23651 54930 21.7423 16.00 75 9.80 102 21.21 33 25.71 35 36 23654 61000 26.09 23 5.26 1932.99 97 18 16.67 18 23654 61000 26.09 23 5.26 19 32.99 97 18 16.67 1823654 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23654 61000 26.09 235.26 19 32.99 97 18 16.67 18 23656 60741 23 47.37 19 22.68 97 33.33 1818 23660 62615 21.74 23 15.79 19 97 5.56 18 5.56 18 23660 62615 21.74 2315.79 19 97 5.56 18 5.56 18 23661 35056 4.35 23 30.67 75 1.96 102 54.5533 36.11 36 36 23666 61035 17.39 23 15.79 19 22.68 97 5.56 18 18 2366661035 17.39 23 15.79 19 22.68 97 5.56 18 18 23667 10592 23 24.68 77 10212.12 33 16.67 36 36 23667 10592 23 24.68 77 102 12.12 33 16.67 36 3623673 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23673 244038.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23676 24511 23 9.38 644.00 100 24.24 33 26.09 23 4.35 23 23679 52789 17.39 23 6.67 75 4.90 10221.21 33 8.57 35 36 23681 35754 23 20.00 75 2.94 102 30.30 33 36.11 3636 23681 36946 23 24.00 75 1.96 102 18.18 33 30.56 36 2.78 36 2368135754 23 20.00 75 2.94 102 30.30 33 36.11 36 36 23681 36946 23 24.00 751.96 102 18.18 33 30.56 36 2.78 36 23681 34559 23 30.67 75 1.96 10230.30 33 33.33 36 5.56 36 23687 62019 30.43 23 19 97 18 18 23687 6201930.43 23 19 97 18 18 23688 35056 4.35 23 30.67 75 1.96 102 54.55 3336.11 36 36 23698 65508 30.43 23 19 12.37 97 18 18 23698 35939 26.09 2375 9.80 102 33 8.33 36 36 23698 55189 26.09 23 5.26 19 8.16 98 17 1823698 65508 30.43 23 19 12.37 97 18 18 23698 54046 26.09 23 75 14.71 1023.03 33 35 2.78 36 23700 62439 21.74 23 19 97 18 18 23700 62439 21.74 2319 97 18 18 23701 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 2323702 61479 26.09 23 63.16 19 3.09 97 61.11 18 18 23702 33688 17.39 2321.05 76 0.98 102 15.15 33 34.29 35 2.78 36 23702 54586 17.39 23 12.0075 102 6.06 33 31.43 35 36 23702 51783 21.74 23 38.67 75 1.96 102 30.3033 57.14 35 36 23702 17831 22.22 18 39.02 41 1.56 64 40.00 30 54.55 119.09 11 23704 60458 4.35 23 57.89 19 25.77 97 61.11 18 18 23704 604584.35 23 57.89 19 25.77 97 61.11 18 18 23704 60458 4.35 23 57.89 19 25.7797 61.11 18 18 23704 60458 4.35 23 57.89 19 25.77 97 61.11 18 18 2370624511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23707 24511 23 9.3864 4.00 100 24.24 33 26.09 23 4.35 23 23712 24511 23 9.38 64 4.00 10024.24 33 26.09 23 4.35 23 23713 51042 26.09 23 2.67 75 3.92 102 3.03 3335 36 23713 51042 26.09 23 2.67 75 3.92 102 3.03 33 35 36 23715 24511 239.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23717 24511 23 9.38 64 4.00100 24.24 33 26.09 23 4.35 23 23718 62439 21.74 23 19 97 18 18 2371862439 21.74 23 19 97 18 18 23719 9191 21.74 23 55.84 77 3.92 102 39.3933 58.33 36 11.11 36 23727 11583 21.74 23 44.16 77 1.96 102 27.27 3366.67 36 2.78 36 23727 37868 26.09 23 49.33 75 4.90 102 36.36 33 55.5636 5.56 36 23727 37868 26.09 23 49.33 75 4.90 102 36.36 33 55.56 36 5.5636 23727 35285 30.43 23 56.00 75 2.94 102 33.33 33 52.78 36 8.33 3623727 35285 30.43 23 56.00 75 2.94 102 33.33 33 52.78 36 8.33 36 2372711583 21.74 23 44.16 77 1.96 102 27.27 33 66.67 36 2.78 36 23733 919121.74 23 55.84 77 3.92 102 39.39 33 58.33 36 11.11 36 23737 62615 21.7423 15.79 19 97 5.56 18 5.56 18 23737 62615 21.74 23 15.79 19 97 5.56 185.56 18 23741 63119 26.09 23 19 1.03 97 18 22.22 18 23741 63119 26.09 2319 1.03 97 18 22.22 18 23746 24511 23 9.38 64 4.00 100 24.24 33 26.09 234.35 23 23749 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 2375760741 23 47.37 19 22.68 97 33.33 18 18 23759 9191 21.74 23 55.84 77 3.92102 39.39 33 58.33 36 11.11 36 23761 64570 4.35 23 19 20.62 97 5.56 1816.67 18 23761 64570 4.35 23 19 20.62 97 5.56 18 16.67 18 23763 4066 828.57 35 11.76 34 26.67 30 42.86 7 7 23763 4066 8 28.57 35 11.76 3426.67 30 42.86 7 7 23763 46009 23 30.26 76 8.82 102 21.21 33 51.43 355.56 36 23763 1542 8 54.29 35 20.59 34 40.00 30 57.14 7 7 23763 1542 854.29 35 20.59 34 40.00 30 57.14 7 7 23763 1542 8 54.29 35 20.59 3440.00 30 57.14 7 7 23764 24511 23 9.38 64 4.00 100 24.24 33 26.09 234.35 23 23765 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 2376524403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23767 61035 17.3923 15.79 19 22.68 97 5.56 18 18 23767 61035 17.39 23 15.79 19 22.68 975.56 18 18

TABLE 160 Colon PROBESET % Breast Breast T/N % Colon M/N Seq Id IdT/N >= 2x Patients M/N >= 2x Patients 23569 3323 24.44 45 44.83 29 2357047141 100.00 12 100.00 11 23571 22807 20.83 48 100.00 23 23572 47166100.00 3 8.33 12 23573 47170 100.00 7 100.00 10 23573 47170 100.00 7100.00 10 23573 47170 100.00 7 100.00 10 23574 54439 100.00 1 15 235753323 24.44 45 44.83 29 23578 47204 100.00 21 27 23581 7337 16.67 18100.00 14 23582 9348 52.27 44 9.52 21 23583 55586 100.00 4 100.00 423584 7337 16.67 18 100.00 14 23587 48770 100.00 3 21.43 28 23589 2673856.00 25 23589 26738 56.00 25 23589 26738 56.00 25 23589 26738 56.00 2523590 48850 4.00 25 50.00 4 23591 35733 100.00 1 77.27 22 23591 35733100.00 1 77.27 22 23592 25507 100.00 22 18.52 27 23593 48810 100.00 4 2823595 35493 48.00 50 3.45 29 23595 35493 48.00 50 3.45 29 23596 5539116.28 43 100.00 1 23597 48850 4.00 25 50.00 4 23600 48901 10.00 20100.00 11 23600 48901 10.00 20 100.00 11 23604 47395 100.00 1 23606 733716.67 18 100.00 14 23608 35013 44 100.00 10 23608 35013 44 100.00 1023609 35493 48.00 50 3.45 29 23609 35493 48.00 50 3.45 29 23610 15407100.00 24 3.85 26 23610 15407 100.00 24 3.85 26 23610 15407 100.00 243.85 26 23610 15407 100.00 24 3.85 26 23611 15407 100.00 24 3.85 2623611 15407 100.00 24 3.85 26 23611 15407 100.00 24 3.85 26 23611 15407100.00 24 3.85 26 23612 15407 100.00 24 3.85 26 23612 15407 100.00 243.85 26 23612 15407 100.00 24 3.85 26 23613 15407 100.00 24 3.85 2623613 15407 100.00 24 3.85 26 23613 15407 100.00 24 3.85 26 23613 15407100.00 24 3.85 26 23613 15407 100.00 24 3.85 26 23613 15407 100.00 243.85 26 23614 55391 16.28 43 100.00 1 23616 15407 100.00 24 3.85 2623616 15407 100.00 24 3.85 26 23616 15407 100.00 24 3.85 26 23616 15407100.00 24 3.85 26 23617 15407 100.00 24 3.85 26 23617 15407 100.00 243.85 26 23617 15407 100.00 24 3.85 26 23618 15407 100.00 24 3.85 2623618 15407 100.00 24 3.85 26 23618 15407 100.00 24 3.85 26 23618 15407100.00 24 3.85 26 23618 15407 100.00 24 3.85 26 23619 15407 100.00 243.85 26 23619 15407 100.00 24 3.85 26 23619 15407 100.00 24 3.85 2623619 15407 100.00 24 3.85 26 23619 15407 100.00 24 3.85 26 23620 15407100.00 24 3.85 26 23620 15407 100.00 24 3.85 26 23620 15407 100.00 243.85 26 23620 15407 100.00 24 3.85 26 23621 15407 100.00 24 3.85 2623621 15407 100.00 24 3.85 26 23621 15407 100.00 24 3.85 26 23621 15407100.00 24 3.85 26 23621 15407 100.00 24 3.85 26 23621 15407 100.00 243.85 26 23621 15407 100.00 24 3.85 26 23621 15407 100.00 24 3.85 2623622 15407 100.00 24 3.85 26 23622 15407 100.00 24 3.85 26 23623 15407100.00 24 3.85 26 23623 15407 100.00 24 3.85 26 23623 15407 100.00 243.85 26 23623 15407 100.00 24 3.85 26 23623 15407 100.00 24 3.85 2623624 15407 100.00 24 3.85 26 23624 15407 100.00 24 3.85 26 23624 15407100.00 24 3.85 26 23624 15407 100.00 24 3.85 26 23625 14582 100.00 542.86 28 23625 14582 100.00 5 42.86 28 23626 15407 100.00 24 3.85 2623626 15407 100.00 24 3.85 26 23626 15407 100.00 24 3.85 26 23626 15407100.00 24 3.85 26 23626 15407 100.00 24 3.85 26 23626 15407 100.00 243.85 26 23626 15407 100.00 24 3.85 26 23627 47141 100.00 12 100.00 1123628 15407 100.00 24 3.85 26 23628 15407 100.00 24 3.85 26 23628 15407100.00 24 3.85 26 23628 15407 100.00 24 3.85 26 23629 54439 100.00 1 1523631 15407 100.00 24 3.85 26 23631 15407 100.00 24 3.85 26 23631 15407100.00 24 3.85 26 23631 15407 100.00 24 3.85 26 23631 15407 100.00 243.85 26 23632 3323 24.44 45 44.83 29 23633 47409 50.00 4 23634 47170100.00 7 100.00 10 23634 47170 100.00 7 100.00 10 23634 47170 100.00 7100.00 10 23635 15407 100.00 24 3.85 26 23635 15407 100.00 24 3.85 2623635 15407 100.00 24 3.85 26 23635 15407 100.00 24 3.85 26 23635 15407100.00 24 3.85 26 23635 15407 100.00 24 3.85 26 23636 35733 100.00 177.27 22 23636 35733 100.00 1 77.27 22 23637 47589 46.51 43 9.09 2223638 47395 100.00 1 23639 15407 100.00 24 3.85 26 23639 15407 100.00 243.85 26 23639 15407 100.00 24 3.85 26 23639 15407 100.00 24 3.85 2623640 15407 100.00 24 3.85 26 23640 15407 100.00 24 3.85 26 23640 15407100.00 24 3.85 26 23640 15407 100.00 24 3.85 26 23641 15407 100.00 243.85 26 23641 15407 100.00 24 3.85 26 23641 15407 100.00 24 3.85 2623641 15407 100.00 24 3.85 26 23642 52781 100.00 19 27 23643 15407100.00 24 3.85 26 23643 15407 100.00 24 3.85 26 23643 15407 100.00 243.85 26 23643 15407 100.00 24 3.85 26 23643 15407 100.00 24 3.85 2623644 15407 100.00 24 3.85 26 23644 15407 100.00 24 3.85 26 23644 15407100.00 24 3.85 26 23644 15407 100.00 24 3.85 26 23645 15407 100.00 243.85 26 23645 15407 100.00 24 3.85 26 23645 15407 100.00 24 3.85 2623647 22180 100.00 5 23647 22180 100.00 5 23648 15407 100.00 24 3.85 2623648 15407 100.00 24 3.85 26 23648 15407 100.00 24 3.85 26 23648 15407100.00 24 3.85 26 23648 15407 100.00 24 3.85 26 23648 15407 100.00 243.85 26 23649 15407 100.00 24 3.85 26 23649 15407 100.00 24 3.85 2623649 15407 100.00 24 3.85 26 23649 15407 100.00 24 3.85 26 23649 15407100.00 24 3.85 26 23649 15407 100.00 24 3.85 26 23650 15407 100.00 243.85 26 23650 15407 100.00 24 3.85 26 23650 15407 100.00 24 3.85 2623650 15407 100.00 24 3.85 26 23652 26408 16.00 50 56.00 25 23652 2640816.00 50 56.00 25 23653 19860 16.33 49 65.52 29 23655 47444 44 74.07 2723657 38650 24.14 29 100.00 1 23657 38650 24.14 29 100.00 1 23658 29692100.00 12 16 23658 29692 100.00 12 16 23659 35013 44 100.00 10 2365935013 44 100.00 10 23662 47338 100.00 2 25.00 4 23663 48850 4.00 2550.00 4 23664 54961 100.00 28 7.14 28 23665 26394 68.00 50 34.48 2923668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23668 15407100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23668 15407 100.00 243.85 26 23668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 2623668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23668 15407100.00 24 3.85 26 23669 15407 100.00 24 3.85 26 23669 15407 100.00 243.85 26 23669 15407 100.00 24 3.85 26 23670 15407 100.00 24 3.85 2623670 15407 100.00 24 3.85 26 23671 15407 100.00 24 3.85 26 23671 15407100.00 24 3.85 26 23671 15407 100.00 24 3.85 26 23672 15407 100.00 243.85 26 23672 15407 100.00 24 3.85 26 23672 15407 100.00 24 3.85 2623672 15407 100.00 24 3.85 26 23672 15407 100.00 24 3.85 26 23674 55038100.00 8 6.67 15 23675 48810 100.00 4 28 23677 15407 100.00 24 3.85 2623677 15407 100.00 24 3.85 26 23677 15407 100.00 24 3.85 26 23678 15407100.00 24 3.85 26 23678 15407 100.00 24 3.85 26 23678 15407 100.00 243.85 26 23678 15407 100.00 24 3.85 26 23680 47668 39.53 43 50.00 2823682 47958 42 77.78 27 23683 47166 100.00 3 8.33 12 23718 52866 18.1844 87.50 8 23719 3323 24.44 45 44.83 29 23720 48070 100.00 2 16.67 1823721 35493 48.00 50 3.45 29 23721 35493 48.00 50 3.45 29 23722 15407100.00 24 3.85 26 23722 15407 100.00 24 3.85 26 23722 15407 100.00 243.85 26 23722 15407 100.00 24 3.85 26 23722 15407 100.00 24 3.85 2623723 3323 24.44 45 44.83 29 23724 55586 100.00 4 100.00 4 23725 15407100.00 24 3.85 26 23725 15407 100.00 24 3.85 26 23725 15407 100.00 243.85 26 23725 15407 100.00 24 3.85 26 23725 15407 100.00 24 3.85 2623726 48510 100.00 6 3.57 28 23728 28027 26.09 46 4.35 23 23728 2802726.09 46 4.35 23 23729 14582 100.00 5 42.86 28 23729 14582 100.00 542.86 28 23730 26408 16.00 50 56.00 25 23731 47395 100.00 1 23732 4740950.00 4 23733 3323 24.44 45 44.83 29 23734 47444 44 74.07 27 23735 22963100.00 1 23736 3323 24.44 45 44.83 29 23684 48850 4.00 25 50.00 4 2368520206 100.00 4 22 23686 35206 47 100.00 2 23687 55391 16.28 43 100.00 123689 28027 26.09 46 4.35 23 23689 28027 26.09 46 4.35 23 23689 2802726.09 46 4.35 23 23690 47589 46.51 43 9.09 22 23691 47170 100.00 7100.00 10 23691 47170 100.00 7 100.00 10 23692 47615 34.09 44 100.00 1723693 14582 100.00 5 42.86 28 23693 14582 100.00 5 42.86 28 23694 47644100.00 6 25.93 27 23695 47589 46.51 43 9.09 22 23696 54439 100.00 1 1523697 47682 31.58 19 50.00 16 23697 47682 31.58 19 50.00 16 23699 4740950.00 4 23700 52866 18.18 44 87.50 8 23738 52781 100.00 19 27 23739 330850.00 16 29 23740 47958 42 77.78 27 23742 47958 42 77.78 27 23743 9939100.00 2 29 23744 47958 42 77.78 27 23745 48510 100.00 6 3.57 28 237467337 16.67 18 100.00 14 23747 48070 100.00 2 16.67 18 23748 48510 100.006 3.57 28 23749 7337 16.67 18 100.00 14 23750 22180 100.00 5 23750 22180100.00 5 23751 47170 100.00 7 100.00 10 23751 47170 100.00 7 100.00 1023752 35682 100.00 6 29 23753 48220 100.00 6 3.57 28 23701 7337 16.67 18100.00 14 23703 48261 100.00 3 100.00 1 23705 54961 100.00 28 7.14 2823707 7337 16.67 18 100.00 14 23708 54795 100.00 1 100.00 1 23709 52709100.00 4 100.00 4 23710 48510 100.00 6 3.57 28 23711 4308 100.00 2 2371455038 100.00 8 6.67 15 23716 35013 44 100.00 10 23716 35013 44 100.00 1023754 54961 100.00 28 7.14 28 23755 52781 100.00 19 27 23756 48510100.00 6 3.57 28 23758 19201 30 44.44 9 23759 3323 24.44 45 44.83 2923760 48580 100.00 4 26 23762 55038 100.00 8 6.67 15 23766 48716 100.006

Those skilled in the art will recognize, or be able to ascertain, usingnot more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such specific embodimentsand equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

1. An isolated polynucleotide comprising at least 15 contiguousnucleotides of a sequence selected from the group consisting of SEQ IDNOS:1-23767 and complements thereof.
 2. A vector comprising thepolynucleotide of claim
 1. 3. A host cell comprising the vector of claim2.
 4. An isolated polynucleotide comprising at least 15 contiguousnucleotides of any one of SEQ ID NOS:1-23767 and which hybridizes understringent conditions to a polynucleotide of a sequence selected from thegroup consisting of SEQ ID NOS:1-23767 and complements thereof.
 5. Anisolated polynucleotide comprising at least 15 contiguous nucleotides ofeither strand of a nucleotide sequence of an insert contained in avector deposited as clone number XXX-YYY of ATCC Deposit Number ZZZ. 6.An isolated polynucleotide comprising at least 15 contiguous nucleotidesof any one of SEQ ID NOS:1-23767, said polynucleotide obtained byamplifying a fragment of cDNA using at least one polynucleotide primercomprising at least 15 contiguous nucleotides of a nucleotide sequenceselected from the group consisting of SEQ ID NOS:1-23767 and complementsthereof.
 7. A method for detecting a cancerous cell, said methodcomprising: detecting a level of a gene product corresponding to any oneof SEQ ID NOS:1-23767 and complements thereof, and comparing the levelof gene product to a control level of said gene product; wherein thepresence of a cancerous cell is indicated by detection of said level andcomparison to a control level of gene product
 8. The method of claim 7,wherein said cancerous cell is a cancerous breast, colon or prostatecell cell.
 9. The method of claim 7, wherein said gene product isnucleic acid.
 10. The method of claim 7, wherein said gene product is apolypeptide.
 11. The method of claim 7, wherein said detecting step usesa polymerase chain reaction.
 12. The method of claim 7, wherein saiddetecting step uses hybridization.
 13. The method of claim 7, whereinsaid sample is a sample of tissue suspected of having cancerous cells.14. A method for inhibiting a cancerous phenotype of a cell, said methodcomprising: contacting a cancerous mammalian cell with an agent forinhibition of a gene product corresponding to any one of SEQ IDNOS:1-23767.
 15. The method of claim 14, wherein said cancerousphenotype is aberrant cellular proliferation relative to a normal cell.16. The method of claim 14, wherein said cancerous phenotype is loss ofcontact inhibition of cell growth.
 17. The method of claims 14, whereinsaid agent is selected from the group consisting of a small molecule, anantibody, an antisense polynucleotide, and an RNAi molecule.
 18. Themethod of claims 14, wherein said inhibition is associated with areduction in a level of a gene product corresponding to any one of SEQID NOS:1-23767.
 19. A method of treating a subject with cancer, saidmethod comprising: administering to a subject a pharmaceuticallyeffective amount of an agent, wherein said agent modulates the activityof a gene product corresponding to any one of SEQ ID NOS:1-23767. 20.The method of claim 19, wherein said agent is selected from the groupconsisting of a small molecule, an antibody, an antisensepolynucleotide, and an RNAi molecule.
 21. A method for assessing thetumor burden of a subject, said method comprising: detecting a level ofa gene product corresponding to any one of SEQ ID NOS:1-23767 in a testsample from a subject, wherein the level of said gene product in thetest sample is indicative of the tumor burden in the subject.
 22. Amethod for identifying an agent that modulates a biological activity ofa gene product differentially expressed in a cancerous cell as comparedto a normal cell, said method comprising: contacting a candidate agentwith a cell; and detecting modulation of a biological activity of a geneproduct corresponding to any one of SEQ ID NOS:1-23767 relative to alevel of biological activity of the same gene product in the absence ofthe candidate agent.
 23. The method of claim 22, wherein said detectingis by assessing expression of said gene product.
 24. The method of claim23, wherein expression is assessed by detecting a polynucleotide geneproduct.
 25. The method of claim 23, wherein expression is assessed bydetecting a polypeptide gene product.
 26. The method of claim 22,wherein said candidate agent is selected from the group consisting of asmall molecule, an antibody, an antisense polynucleotide, and an RNAimolecule.
 27. The method of claim 22, wherein said biological activityis modulation of a cancerous phenotype.
 28. The method of claim 27,wherein said cancerous phenotype is abnormal cellular proliferation. 29.An isolated antibody that specifically binds to a polypeptide encodingby a polynucleotide consisting of a nucleotide sequence set forth in anyone of SEQ ID NOS:1-23767 and complements thereof.